Reduce Bone Pain Research Articles

Treatment with oxygen-ozone therapy in hemodialysis patients

Peripheral arterial disease and secondary amyloidosis account for significant morbidity and mortality among uremic patients. Several papers demonstrated the beneficial effects of ozone therapy in the treatment of vascular and orthopaedic diseases. The aim of this paper is to study these effects among hemodialysed patients with severe complications. Seventy-five hemodialysed patients were studied. Sixty patients suffered from peripheral arterial occlusive disease. Twenty-three of them underwent previous unilateral lower limb amputation (Group 1). Fifteen subjects had remarkable joint pain due to a2-microglobulin deposition (Group 2). All patients were treated with analgesic therapy. The Italian Society for Oxygen-Ozone Therapy (SIOOT) protocols were applied: the patients received major O3 autohemotherapy, subcutaneous ozone infusion and body exposure to oxygen/ozone mixture by bagging. A questionnaire was submitted to the patients at the beginning and at the end of ozone therapy for the individual assessment of treatment efficacy. Complete healing of the ischemic ulcers was obtained in many patients. Eight-eight percent of the patients reported a subjective successful outcome after ozone therapy. Both Group 1 and Group 2 subjects reported a significant decrease in pain perception. The use of analgesic drugs was reduced in 78% of them and 72% got a normal sleep/wake cycle. An enhancement in physical activity was reported by 67% of the subjects. Ozone therapy improves hemodialysed patients’ quality of life reducing bone pain perception and attenuating clinical signs of peripheral vascular disease.

Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete. To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy. Case series. Academic center of expertise for rare bone diseases. Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months. Sustained reduction of BTMs and bone pain. A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated. Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.

Bone scan index can be a useful biomarker of survival outcomes in patients with metastatic castration-resistant prostate cancer treated with radium-223.

Bone metastasis of prostate cancer is associated with pain and reduced overall survival (OS). Radium-223, which is expected to reduce bone pain and prolong OS, was recently approved in Japan. The aim of this study was to investigate the usefulness of the bone scan index by comparing the outcomes and factors according to response in Japanese patients treated with radium-223. Twenty patients receiving radium-223 were divided into two groups according to whether they did or did not achieve a bone scan index decrease of at least one point (beneficial and non-beneficial groups, respectively). The clinical characteristics at baseline and after three and six treatment cycles were compared using χ2 tests and Student's t-tests or Mann-Whitney U tests, and survival was estimated and compared using the Kaplan-Meier method and log-rank test, respectively. Fourteen (70%) and six patients (30%) were categorized into the beneficial and non-beneficial groups, respectively. Patients in the former group were significantly more likely to have a higher Eastern Cooperative Oncology Group performance status score and receive a greater number of radium-223 injections (P<0.05). Furthermore, patients in the beneficial group had a significantly longer OS (P<0.05). Regarding safety, one and three patients in the beneficial and non-beneficial groups, respectively, prematurely discontinued radium-223 because of an increased prostate-specific antigen level, decreased hemoglobin level, or femoral fracture. Radium-223 appears generally safe in this population. Patients with good bone scan index response have better performance status, receive more injections of radium-223, and achieve OS prolongation. Bone scan index is a useful biomarker of survival outcomes and can be a valuable assessment tool in patients with metastatic castration-resistant prostate cancer who are treated with radium-223.

Improvements in bone pain and patient quality of life in adults with Gaucher disease during substrate reduction therapy: a case series

Background: Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by a deficiency of glucocerebrosidase, and is characterised by haematological, visceral and bone manifestations that vary widely in terms of severity and age at onset. In particular, the bone manifestations of GD1 can restrict physical activity and impact heavily on patient quality of life (QoL). Here, we describe three GD1 patients who showed remarkable improvements in bone-related outcomes during treatment with oral miglustat, two of whom had previously failed to respond to relatively high doses of enzyme replacement therapy (ERT). In the third, needle phobia led to oral miglustat being used as the initial treatment.&#x0D; Case presentation: Case 1 is a 39 year-old female diagnosed aged 4 years (genotype N370S/L444P) and underwent ERT (alglucerase then imiglucerase) since 1994. In 2013 she discontinued ERT (treatment duration 19 years) due to ongoing and debilitating bone pain and fatigue, and switched to miglustat therapy. She has since experienced substantial reductions in bone pain and improved physical function. Case 2 is a 59 year-old female diagnosed aged 17 years (genotype N370S/H162P). She commenced ERT treatment in 2002, with a brief interruption in 2007, and continued on ERT (imiglucerase followed by velaglucerase) up to 2014: total ERT monotherapy duration 12 years. She subsequently received combination therapy (velaglucerase plus miglustat) for 2 years but finally switched to miglustat monotherapy in 2016 due to ongoing bone manifestations. Her bone pain has since improved a great deal, alongside improvements in QoL parameters. Case 3 is a 48 year-old male diagnosed aged 11 years (genotype R463C/L105R). Having not received any previous treatment he avoided ERT due to life-long needle phobia. He therefore started miglustat therapy in late-2017, and has received it for approximately 1 year. During this time he experienced vast improvements in QoL due to decreased bone pain. Interestingly in all three cases, there were little or no observed changes in objective bone parameters (bone marrow burden, bone mineral density).&#x0D; Conclusions: These three GD1 cases illustrate the potential to achieve substantial reductions in bone pain and improvements in QoL, even in patients who have failed to respond to long-term ERT with regard to bone status.

Effect of wet cupping on reducing bone pain for patients in King Abdulaziz University Hospital, Saudi Arabia. A retrospective study.

Objectives:To investigate the effectiveness of wet cupping as alternative treatment on reducing bone pain and built a model that predicts the level of improvement for patients who suffer from bone pain.Methods:This retrospective study was conducted on 289 patients referred from specialty clinics to Prophetic Medicine Clinics (PMC) between September 2013 and August 2015. The effectiveness of cupping is assessed on patients with bone pain who were redirected to PMC, King Abdulaziz University Hospital, Jeddah, Saudi Arabia. An artificial neural network (ANN) method was used to propose a model that predicts levels of improvement for patients suffering from bone pain. Therefore, a random sample of 90% of the data was used to build the ANN model and tested by the remaining 10%. Inferential statistics were conducted to study relations and compare blood tests before and after treatment.Results:Out of 289 patients suffering from bone pain, more than 11% were completely cured, and 55% improved after wet cupping treatment sessions. The proposed ANN model showed a good performance with more than 72% accuracy. In addition, the statistical analysis showed a significant improvement for most blood tests.Conclusion:Wet cupping has positive effects on reducing bone pain. We recommend the use of an ANN model in PMC to predict whether patients will benefit from the treatment to reduce pain. This is a recommendation for further study not a conclusion.

Zoledronic Acid Modulation of TRPV1 Channel Currents in Osteoblast Cell Line and Native Rat and Mouse Bone Marrow-Derived Osteoblasts: Cell Proliferation and Mineralization Effect.

Bisphosphonates (BPs) reduce bone pain and fractures by balancing the osteoblast/osteoclast ratio. The behavior of ion channels in the presence of BPs is not known. To investigate this, the effect of zoledronic acid BP (ZOL) (3 × 10−8 to 5 × 10−4 M) treatment, on ion channels, cell proliferation, and mineralization, has been investigated on preosteoclast-like cells, RAW264.7, preosteoblast-like cells MC3T3-E1, and rat/mouse native bone marrow-derived osteoblasts. In whole-cell patch clamp on cell line- and bone marrow-derived osteoblasts, ZOL potentiated outward currents. On RAW264.7, ZOL (10−4 M)-evoked current was reduced by the Kv channel blocker tetraethylammonium hydrochloride (TEA), but not by the selective TRPV1-channel antagonist capsazepine. On MC3T3-E1 cells and bone marrow-derived osteoblasts, ZOL-evoked current (5 × 10−8 to 10−4 M) was reduced by capsazepine, whereas the selective TRPV1-channel agonist capsaicin potentiated the control current. In the cell proliferation assay, 72 h incubation of RAW264.7 and MC3T3-E1 cells with ZOL reduced proliferation, with IC50 values of 2.62 × 10−7 M and 2.02 × 10−5 M, respectively. Mineralization of MC3T3-E1 cells and bone marrow-derived osteoblasts was observed in the presence of capsaicin and ZOL (5 × 10−8–10−7 M); ZOL effects were antagonized by capsazepine. In summary, the ZOL-induced activation of TRPV1 channel mediates the mineralization of osteoblasts and counterbalances the antiproliferative effects, increasing the IC50. This mechanism is not operative in osteoclasts lacking the TRPV1 channel.

Manifestations osseuses de la maladie de Gaucher

Gaucher disease is a rare, multi-system disease caused by a genetic deficiency of lysosomal glucocerebrosidase. Glucocerebroside accumulates in cells of the reticuloendothelial system leading to chronic macrophage activation, bone marrow infiltration, organ enlargement (liver and spleen), and cytopenia. Skeletal manifestations are often the most striking and disabling long-term consequence of Gaucher disease type 1; clinical or radiographic evidence of bone disease has been reported in 70–100% of diagnosed patients. Avascular osteonecrosis of the hip is the most disabling complication with early bone pain and often joint collapse and secondary osteoarthritis needing orthopaedic interventions in young adults. Localized or systemic bone fragility explains osteopenia, osteoporosis and fractures. Although no double-blind randomized studies have been performed to evaluate bone effect of the treatments, enzyme replacement therapy has demonstrate its efficacy in naïve patients reducing bone pain in about 50% of patients within 1 to 2 years, improving bone mineral density after at least 3 years of treatment. Substrate reduction therapy is an alternative treatment approach. Specific treatment of bone fragility needs a rigorous evaluation with assessment of other risk factors.

Bisphosphonates and other bone agents for breast cancer.

Background Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab, inhibit key pathways in the vicious cycle of bone metastases. Objectives To assess the effect of bisphosphonates on skeletal-related events (SREs), bone pain, quality of life (QoL), recurrence and survival in women with breast cancer with bone metastases (BCBM), advanced breast cancer (ABC) without clinical evidence of bone metastases and early breast cancer (EBC). To assess the effect of denosumab on SREs, bone pain and (QoL) in women with (BCBM). Search methods We searched the Specialised Register maintained by the Cochrane Breast Cancer Group (CBCGSR), MEDLINE, EMBASE and the WHO International Cancer Trials Registry Platform (WHO ICTRP) on 30 April 2011. We conducted additional handsearching of journals and proceedings of key meetings. Selection criteria We included randomised controlled trials (RCTs) comparing: (a) bisphosphonates and control, or different bisphosphonates in women with BCBM; (b) denosumab and bisphosphonates in women with BCBM; (c) bisphosphonates and control in women with ABC; (d) bisphosphonates and control in women with EBC; and (e) early versus delayed bisphosphonate treatment in women with EBC. Data collection and analysis Two review authors (MW and NP) independently assessed the trials and extracted the data. We collected toxicity information from the trials. Main results We included thirty-four RCTs. In nine studies (2806 patients with BCBM), comparing bisphosphonates with placebo or no bisphosphonates, bisphosphonates reduced the SRE risk by 15% (risk ratio (RR) 0.85; 95% confidence interval (CI) 0.77 to 0.94; P = 0.001). This benefit was most certain with intravenous (i.v.) zoledronic acid (4 mg) (RR 0.59; 95% CI 0.42 to 0.82); i.v. pamidronate (90 mg) (RR 0.77; 95% CI 0.69 to 0.87); and i.v. ibandronate (RR 0.80; 95% CI 0.67 to 0.96). A direct comparison of i.v. zoledronic acid and i.v. pamidronate confirmed at least equivalent efficacy in a single large study. In three studies (3405 patients with BCBM), compared with bisphosphonates, subcutaneous (s.c.) denosumab was more effective in reducing the risk of SREs (RR 0.78; 95% CI 0.72 to 0.85; P < 0.00001). Bisphosphonates reduced the SRE rate in 12 studies (median reduction 28%, range 14% to 48%), with statistically significant reductions reported in 10 studies. Women with BCBM treated with bisphosphonates showed significant delays in the median time to SREs. Compared with placebo or no bisphosphonates, treatment with bisphosphonates significantly improved bone pain in six out of eleven studies. Improvements in global QoL with bisphosphonates compared to placebo were reported in two out of five studies (both ibandronate studies). Treatment with bisphosphonates did not appear to affect survival in women with BCBM. Compared to i.v. zoledronic acid, denosumab also significantly reduced the SRE rate, delayed the time to SREs and prolonged the time in developing pain for patients with no or mild pain at baseline; but there was no difference in survival between patients treated with denosumab and zoledronic acid. Bisphosphonates in women with ABC without clinically evident bone metastases did not reduce the incidence of bone metastases, or improve survival in three studies (320 patients). In seven studies (7847 patients with EBC), currently there is no evidence supporting bisphosphonates in reducing the incidence of bone metastases compared to no bisphosphonates (RR 0.94; 95% CI 0.82 to 1.07; P = 0.36). In three studies (2190 patients with EBC), early bisphosphonate treatment also did not significantly reduce the incidence of bone metastases compared to delayed bisphosphonate treatment (RR 0.73; 95% CI 0.40 to 1.33; P = 0.31). Currently, there is insufficient evidence to make a conclusion about the role of adjuvant bisphosphonates in reducing visceral metastases, locoregional recurrence and total recurrence, or improving survival. There was strong heterogeneity in EBC studies examining the outcomes of total recurrence and survival. Reported toxicity was generally mild. Renal toxicity and osteonecrosis of the jaw (ONJ) have been identified as potential problems with bisphosphonate use. ONJ was reported at similar rates for patients on denosumab compared to zoledronic acid. This highlighted a need for maintaining good oral care, prior to and during treatment, for patients who received long-term bone agents. Authors' conclusions In women with clinically evident BCBM, bisphosphonates (oral and i.v.) and denosumab (s.c.) reduced the risk of developing SREs, as well as delaying the time to SREs. Some bisphosphonates may also reduce bone pain and may improve QoL. The optimal timing and duration of treatment for patients with BCBM remains uncertain. There is currently insufficient evidence to support the routine use of bisphosphonates as adjuvant treatment for patients with EBC. However, a number of large clinical trials investigating bisphosphonates in EBC have completed accrual and are awaiting results.

Bone Cancer Pain Effective Management: A Review

Methodology: Pain is most symptom effect of cancer patient, the effect managements is significant topic for highlighted, this paper aims to review critically to identify the effective pain management but on specify bone cancer pain, studies published between 2009 and 2014 were retrieved by searching pubmed electronic databases, identified 14 studies that met the inclusion criteria. Results: Management of bone cancer pain have multidisciplinary pharmacological one of type of managements, the usage of medication have a cost effective and safe to patient and control pain, the biophophonate family show effective management but there difference on potency among group, the biophophonate family have different route. Oral and iv, both safe however both oral and i.v. therapies have disadvantages but was acceptable to most patients some of whom had reduced bone pain over time. Net result more data regarding acceptability, adherence, and patients’ preference for bisphosphonate therapies are required choice also, the treatment of bone cancer pain before once to have effective result, research divided to, research on zoledronic acid, other comparzim othor modality, and the finding was a significant reduction on pain by using biophophamte treatment. Conclusion: As results differ, critical and specific group analysis of management aspect , motivations to provide initial treatment, improving awareness, provide for patient route that prefer is recommended. Provide initial treatment, improving awareness, provide for patient route that prefer is recommended

Dramatic mitigation of bone pain after phosphorus replacement therapy in a subject with FGF23-related hypophosphatemic osteomalacia.

IntroductionFibroblast growth factor 23 (FGF23) is secreted from bone and suppresses the absorption of phosphorus in renal proximal tubule and in intestinal tract. Therefore, the increase of serum FGF23 levels leads to hypophosphatemic situations. Tumor-induced osteomalacia is often induced by various tumors, but it is often difficult to identify the localization of tumor, because most of the FGF23-producing tumors are small and could be observed in any part of the body.Case descriptionHere we report a case of elderly female subject with FGF23-related hypophosphatemic osteomalacia who repeatedly experienced severe bone pain and fragility fracture in various parts of the body. Although we failed to identify the localization of tumor in this subject even with various examination, after starting phosphorus replacement therapy with relatively small amounts of calcium phosphate (1.5 g/day) (phosphorus content: 270 mg), hypophosphatemia was ameliorated and repeated bone pain was dramatically mitigated without any surgical operation.Discussion and EvaluationEven when we fail to identify the localization of tumor in subjects with FGF23-related hypophosphatemic osteomalacia, phosphorus replacement therapy for hypophosphatemia could reduce the bone pain.ConclusionsWe should be aware of the possibility that phosphorus replacement therapy exert marked beneficial effects for the reduction of bone pain in subjects with FGF23-related hypophosphatemic osteomalacia even when we fail to identify tumor localization.

Difficulties in the management of hypophosphatemic rickets in adulthood

Introduction. The therapeutic management of hypophosphatemic rickets in adulthood aims to reduce bone pain, the extent of osteomalacia and improve fracture healing and surgical recovery, but clinicians need to stay alert as potential risks can sometimes exceed the benefits of treatment.Case report. We present the case of a 25 year old male patient who was admitted in our department for evaluation presenting severe bone pain. From his medical history we mention that he was diagnosed with rickets at the age of 3 years and received treatment with vitamin D and calcium with no clinical response. A corrective surgery for femur valgus was performed two years later. Because he received high doses of vitamin D without improvement of symptoms the suspicion of vitamin D-resistant rickets was raised at the age of 12 years and treatment with calcitriol 3 tb/day was started with a decline of alkaline phosphatase level from 1144 to 509 UI/l. Two years ago he was diagnosed with renal microlitiasis and left tibial fracture. At present admission he presented with disarmonic short stature, H=149.4 cm (-4.14 SD), W=59 kg, macrocephaly, dental dystrophy and leg bowing. He was under chronic treatment with active vitamin D analog 2 tb/day. Laboratory tests revealed low phosphate (P=2 mg/dl), low 25-OH-vitamin D (19 ng/ml) and 1,25-(OH)2-vitamin D (13.2 pg/ml), normal serum and urinary calcium, normal PTH, high beta crosslaps. In order to diagnose hypophosphatemic rickets, serum FGF23 analysis was performed and it was elevated , but the genetic testing for hypophosphatemic rickets was not available. Because the patient had severe bone pain, a tibial fracture and intented to perform a corrective osteotomy we decided to start medical treatment with elemental phosphorus for 9-12 months, at least 3-6 months before surgery with strict monitoring of serum and urinary calcium and phosphate level, creatinine, alkaline phosphatase and serum PTH.Conclusion. The key point of the case is the late diagnosis of hypophosphatemic rickets and the challenge in treating our patient in order to minimize the risks of combined treatment with calcitriol and phosphorus giving the fact that he was already diagnosed with nephromicrolitiasis.

Le traitement des métastases osseuses par radiopharmaceutiques à tropisme osseux

Bone seeking radiopharmaceutics are often used in patients with skeletal lesions during the diagnostic and, less frequently, the therapeutic setting. The aim of the radionuclide therapy in patients with bone metastases is to release the maximum of the energy on neoplastic cells, with the minimum of toxicity for the remnant bone cells and extracellular environment. The radionuclides used in nuclear medicine therapy could be β-emitters, such as 131iodine, 90ytrium, 188rhenium, 186rhenium, 177lutetium, 89strontium and 153samarium, α emitters, such as 223radium, 211actinium, 212bismuth or Auger electron emitters, such as 125iodine and 111indium. To date, 89strontium chloride and 153samarium ethylene diamine tetramethylene bisphosphonate are successfully used for palliative treatment in patients with bone metastases from prostate cancer; moreover, 153samarium can be used also in osteoblastic metastases derived from other neoplasms. Recently, 223RaCl2 a “new” agent has been shown to be useful not only to prolong overall survival of patients with bone metastases from prostate cancer, but also to extend the delay of symptomatic skeletal events, to reduce bone pain and to reduce need for external beam radiation therapy in order to treat bone pain. Therefore, to date 223RaCl2 is recommended in the treatment of castrate resistant prostate cancer by international clinical guidelines. Potential benefits of 223RaCl2 in patients with metastases from other neoplasms are currently under investigation and results will be available very soon.

C21 - First Italian Multicentre Experience in using Ra-223 in patients with metastatic castration resistant prostate cancer (mCRPC)

Aim: Radium-223 is a novel bone-targeted &agr;-emitter associated with a survival benefit. We present first Italian multicentre experience in using Ra-223 in mCRPC patients. Material and methods: Data from mCRPC pts submitted to Ra-223 treatment over 3 years (August 2013-February 2016) were retrospectively collected. Information included Gleason score, age, prior treatments, bone symptoms, analgesic requirements, imaging and blood results. Ra-223 (50 kBq/kg) was administered every 4 weeks, up to the recommended 6 therapy cycles. Endpoints assessed included Overall Survival, pain score using Visual Analog scale (VAS), side effects, skeletal related events (SREs), disease biomarkers (PSA & ALP levels) and haematological parameters. Results: 90 pts received Ra-223 in three Italian Oncology/Radiotherapy/Nuclear Medicine Departments. Up to April 2016 only Pisa Departments data are available. Median age was 69 yr (range 52-85 yr). Median follow-up was 8,6 months (range 1-18 months). Mean Gleason score was 7. All patients received 3 previous lines of treatment on average. All bone scans showed foci of abnormal uptake. CT scans was used to exclude visceral involvement and the presence of pathologic lymph nodes with a diameter = 3 cm. 16/32 pts completed the recommended 6 cycles, of whom: 5 had bone pain reduction, 3 had worsening, 8 had absence of bone pain, remaining stable and not requiring analgesia. 16 pts stopped treatment : 3 cases of delay due to lack in radiopharmaceutical supplies, 9 developed extra skeletal disease/skeletal progression, 3 deteriorated clinically, 1 experienced SRE during treatment. About non-haematological toxicity we observed 3 cases of G3 anorexia, 3 cases of G1 diarrhoea, 2 cases of G2 asthenia. No patients developed SREs during follow-up. Concerning haematological toxicity, bone marrow failure resulted in 8 cases of G2 anaemia, 6 cases of G3 anaemia, 2 cases of G2 leucopoenia, 1 case of G2 thrombocytopenia. Regarding biomarkers, median ALP decline was 50%, median LDH decline was -5%, 32% of pts showed a reduction in PSA level. OS mean is at the present date about 8 months, and median OS has not been achieved yet. Conclusion: Ra-223 has a major impact on serum ALP levels, with negligible effect on PSA levels. Therefore, ALP appears to be a useful biomarker of therapy response. Haematological and non-haematological side effects were acceptable. Stability in pain or palliative effects occurred in the majority of patients.

Ibandronate: The loading dose concept in the treatment of metastatic bone pain

Background/AimSevere bone pain is experienced by 60–80% of patients with metastatic bone disease, and has a profound impact on quality of life. Therefore, effective pain relief is an important goal in managing metastatic bone disease. Orthopedic surgeons are often challenged with patients presenting with newly diagnosed bone metastases and severe and disabling bone pain. It is important to provide fast and sufficient analgesia. Clinical trials have demonstrated that bisphosphonates reduce effectively and sustained bone pain by approved standard dosage over time. Open label prospective trials have shown that short time high dose i.v. Ibandronate is effective in rapid pain relief in different primary tumors. Patients and methodsIn 33 patients with metastatic bone pain from newly diagnosed skeletal metastases we utilized the loading-dose concept for intravenous ibandronate (6mg infused over 1h on 3 consecutive days). ResultsIn 33 patients loading-dose ibandronate therapy significantly reduced bone pain within the first 5–7 days (VAS day 0: 6–8 vs. day 7: 3–4). Only 3 patients showed no response concerning a distinct pain reduction within the first days of therapy. There was no increase in pain medication. ConclusionThis clinical observational study in selected patients with severe metastatic bone pain undergoing an intensive high dosed ibandronate-therapy for a short period demonstrated that loading-dose ibandronate (6mg i.v., 3 consecutive days) resulted in a reduction of pain within days.

Bone targeting agent treatment patterns and the impact of bone metastases on patients with advanced breast cancer in the US.

93 Background: Bone is the most common site of distant metastasis in patients with advanced breast cancer. Bone metastases (BMs) often lead to skeletal-related events (SREs) and may result in debilitating bone pain which impacts a patient’s quality of life. Bone targeting agents (BTAs) reduce the incidence of SREs and progression of pain due to BMs. This study aims to understand real world patients’ experience of bone pain and to assess BTAs treatment patterns. Methods: Data were extracted from the Adelphi Breast Cancer Disease-Specific Programme (DSP), a cross-sectional survey of 98 US oncologists conducted from February to May 2015 in the USA. Each physician completed comprehensive record forms capturing the following information about the next 12 patients being treated for advanced breast cancer: Presence of BMs, patient’s pain state at diagnosis of BMs, current pain state, time since diagnosis of BMs, current analgesic use and reasons for prescribing BTAs. Results: Bone pain was more prevalent (p &lt; 0.001) in patients with BMs (67% of 485) than those without BM (7% of 791). Mean time for pain assessment was 6.2 months after BM diagnosis. Among breast cancer patients with BMs and bone pain (n = 323), 98% required analgesic medications to manage the pain, including 40% (n = 130) who were treated with strong opioids (e.g., morphine, oxycodone, hydromorphone, or methadone). Of these patients, 100 (77%) had moderate/severe bone pain. Of the patients with BMs, 69% (n = 337) were treated with a BTA and treatment was initiated within 3 months of BMs diagnosis in 91% (n = 306) of them. The reasons for prescribing a BTA within 3 months of BM diagnosis were “bone pain” (32%), “high risk of bone complications” (25%), “prior history of bone complications”(18%), “number of BMs” (11%) and “location of BMs” (4%). Conclusions: Advanced breast cancer patients with BMs are more likely to experience bone pain, and three-fourths of the patients treated with strong opioids experienced moderate/severe bone pain.The majority of patients with BMs receive a BTA prescription for the reduction of bone pain and risk of bone complications.

CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer.

9501 Background: Zoledronic acid (ZA) given monthly for 24 months (mo) reduces bone pain and skeletal-related events (SRE) in patients (pts) with bone metastases. We tested whether ZA every 3 mo wo...

Acidic Extracellular Microenvironment in Myeloma-Colonized Bone Contributes to Bone Pain

Multiple myeloma (MM) bone disease results in devastating bone pain and fractures, which are the major cause of morbidity, and contribute to increased mortality and diminish the quality of life in MM patients. Current treatments for MM bone pain do not completely control the pain and have serious side effects. Thus, new therapies are needed to control myeloma bone pain. However, the mechanisms responsible for MM-associated bone pain are poorly understood. Specific osteoclast inhibitors (bisphosphonates and denosumab) can reduce bone pain in MM patients, suggesting that factors released at the tumor-bone interface during osteoclastic bone resorption may be important contributors to bone pain.Bone-resorbing osteoclasts release protons to dissolve bone minerals and aggressively proliferating tumor cells also release protons/lactate as a consequenece of aerobic glycolysis. Since acidosis is algogenic for primary afferent sensory neurons, we reasoned that an acidic extracellular microenvironment created by the release of protons by osteoclasts and MM cells play a critical role in the pathophysiology of bone pain.To investigate the mechanism of bone pain associated with MM, we used an animal model in which the JJN3 human MM cells were inoculated into the tibiae of SCID mice. Control mice received PBS. Bone pain was assessed by determining tactile hypersensitivity and thermal hyperalgesia of JJN3-bearing mice using von Frey and plantar tests.Administration of the pH probe acridine orange to JJN3-bearing mice revealed that resorption pits beneath bone-resorbing osteoclasts and JJN3-colonized tibiae are acidic. Mice bearing JJN3 MM in their tibiae displayed progressive tactile hypersensitivity and thermal hyperalgesia as the tumor grew. Of note, the bisphosphonate zoledronic acid significantly reduced the progression of the tactile hypersensitivity and thermal hyperalgesia, suggesting that these nociceptive behaviors of JJN3-bearing mice are due to osteoclast-mediated bone pain. Importantly, the non-selective proton pump inhibitor bafilomycin A1 inhibited the creation of the acidic extracellular microenvironment in JJN3-colonized bone and significantly prevented the progression of the nociceptive behaviors. These results support that the acidic extracellular microenvironment is responsible for evoking bone pain. Immunohistochemical examination to identify acid-sensing mechanisms present in bone showed that the calcitonin gene-related peptide (CGRP)-positive sensory neurons innervating bone are adjacent to osteoclasts with co-expression of the acid-sensing nociceptor, the transient receptor potential vanilloid subfamily member 1 (TRPV1). To determine the role of TRPV1 in the excitation of sensory neurons, primary sensory neuron cells isolated from dorsal root ganglion (DRG) were exposed to acidic medium (pH 6.5) and examined for intracellular Ca2+ mobilization using Fura 2 AM calcium imaging assays. Acidic medium induced Ca2+ influx in DRG sensory neuron cells and the induced Ca2+ influx was blocked in the presence of the specific TRPV1 antagonist SB366791, while the specific TRPV4 antagonist RN1734 showed no effect. Further, the specific antagonist for the acid-sensing ion channel 3 (ASIC3), APETx2, also blocked the induction of Ca2+ influx. Neutral medium (pH 7.4) did not induce Ca2+ influx. Taken together, these results suggest that TRPV1 and ASIC3 play an important role in the excitation of sensory neurons exposed to acidic extracellular microenvironment.Our results suggest that the acidic extracellular microenvironments created by protons released from osteoclasts and MM cells excite sensory neurons associated with bone via the acid-sensing nociceptors, TRPV1 and ASIC3, to evoke bone pain. TRPV1 and ASIC3 may be potential targets for ameliorating bone pain in MM. DisclosuresRoodman:Eli Lilly and Co.: Research Funding.

Denosumab improves bone mineral density and microarchitecture and reduces bone pain in women with osteoporosis with and without glucocorticoid treatment

Osteoporosis is a key health problem in postmenopausal women with high social and economic impact. Decreased bone mineral density (BMD) and deterioration of bone microarchitecture may occur also as a result of long-term glucocorticoid treatment (GCT) of autoimmune or inflammatory conditions. Denosumab specifically inhibits the binding of the receptor activator of nuclear factor-κB to its ligand, thus preventing osteoclast activation and bone resorption. The efficacy and safety of denosumab, administered subcutaneously as 60 mg, once every six months for 12 months, were evaluated in 60 patients with postmenopausal osteoporosis (PMO) divided into two groups. The GCT group included 30 patients receiving concomitant glucocorticoid therapy and the non-GCT group included 30 patients that did not receive GCT. In the non-GCT group, the 12-month treatment with denosumab resulted in BMD increase of 6.1% and 2.8% in lumbar spine and hip, respectively. T-score increased by 13.1% and 5.6% in both, the lumbar spine and hip. A slight rise in the Trabecular Bone Score (TBS) of 0.3% was observed. Bone pain was markedly reduced by 56.2%. In the GCT group, denosumab therapy increased BMD with 5.8% and 2.3% in lumbar spine and hip, respectively. T-score of lumbar spine and hip significantly increased by 14.0% and 4.4%, and the TBS rose by 5%. Bone pain was reduced by 53.6%. These data confirm the available knowledge on denosumab efficacy and safety in women with PMO and also provide new insights into its therapeutic potential in patients with osteoporosis related to a long-term corticosteroid treatment.

Bone health in cancer patients: ESMO Clinical Practice Guidelines

There are three distinct areas of cancer management that make bone health in cancer patients of increasing clinical importance. First, bone metastases are common in many solid tumours, notably those arising from the breast, prostate and lung, as well as multiple myeloma, and may cause major morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Through optimum multidisciplinary management of patients with bone metastases, including the use of bone-targeted treatments such as potent bisphosphonates or denosumab, it has been possible to transform the course of advanced cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Secondly, many of the treatments we use to treat cancer patients have effects on reproductive hormones, which are critical for the maintenance of normal bone remodelling. This endocrine disturbance results in accelerated bone loss and an increased risk of osteoporosis and fractures that can have a significant negative impact on the lives of the rapidly expanding number of long-term cancer survivors. Finally, the bone marrow micro-environment is also intimately involved in the metastatic processes required for cancer dissemination, and there are emerging data showing that, at least in some clinical situations, the use of bone-targeted treatments can reduce metastasis to bone and has potential impact on patient survival.

Kidney cancer: bisphosphonates in the era of antiangiogenic targeted therapy.

Bone is the second most common metastatic site in patients presenting with metastatic renal cell carcinoma. Bisphosphonates have been approved to reduce bone pain and the risk of skeletal-related events (SREs) in such patients; however, new research suggests bisphosphonates do not improve survival or prevent development of SREs.