***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: We report the long-term effects of dichloromethylene diphosphonate ( CI2MDP ) , an inhibitor of bone resorption , on the skeletal lesions in multiple myeloma . Thirteen patients received either CI2MDP 1600 mg/d ( seven patients ) or a placebo ( six patients ) in addition to other chemotherapy  , and the effects of treatment were followed over a period of up to 18 months in a double-blind study . CI2MDP treatment result ed in a marked reduction in bone pain , with no progression of radiologic skeletal lesions during the first year . This contrasted with a clinical deterioration and the occurrence of new fractures in half of the patients receiving the placebo . Two patients with  hypercalciuria  and increased excretion of hydroxyproline before treatment had normalized values following CI2MDP . Finally , iliac crest bone biopsies showed a reduction in osteoclast number after CI2MDP administration . We conclude from these results that CI2MDP could be of use in preventing the bone loss that occurs in multiple myeloma PURPOSE To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy . PATIENTS AND METHODS Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were r and omized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles . Patients were evaluated for skeletal complications : pathologic fractures , spinal cord compression , irradiation of or surgery on bone , or hypercalcemia . The skeletal morbidity rate ( the ratio of the number of skeletal complications to the time on trial ) was the primary efficacy variable . Bone pain , use of analgesics , quality of life , performance status , bone tumor response , and biochemical parameters were also evaluated . RESULTS One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable . The skeletal morbidity rate was significantly reduced at 12 , 18 , and 24 cycles in patients treated with 90 mg of pamidronate ( P = .028 , .023 , and .008 , respectively ) . At 24 cycles , the proportion of patients having had any skeletal complication was 56 % in the pamidronate group and 67 % in the placebo group ( P = .027 ) . The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo ( P = .049 ) . There was no statistical difference in survival or in objective bone response rate .  Pamidronate was well tolerated . CONCLUSION Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally r and omized for treatment with clodronate or placebo . Clodronate treatment was started with 5 days intravenous administration ( 300 mg day[-1 ] ) and followed by oral treatment ( 1.6 g day[-1 ] ) for 12 months . Skeletal pain relief was only about 10 % better in the clodronate than in the placebo group . The results do not support the superiority of combined intravenous and oral treatment with  clodronate  compared with oral administration only Abstract The aim of this double-blind , r and omized study was to compare the effects of two pamidronate dosages , given as repeated infusions in patients with advanced malignant osteolytic bone disease and bone pain . Seventy patients were r and omly assigned to receive pamidronate 60 mg or 90 mg i.v . every 3 weeks for a maximum of six cycles . Pain parameters , analgesic consumption and performance status were assessed at baseline and throughout the study . Furthermore , total-body bone mineral density was measured using dual- energy X-ray absorptiometry at baseline , after three and after six infusions . Sixty percent ( 95 % CI 41–77 % ) of the patients in the 60 mg group and 63 % ( 95 % CI 44–79 % ) of the patients in the 90-mg group had a sustained reduction of pain intensity and were classified as pain responders . Median duration of pain response was 15 versus 12 weeks in the 60-mg and 90-mg groups , respectively ( P=0.32 ) . After two infusions , significant changes in pain intensity , pain frequency , general well-being and WHO pain score were observed ( P<0.01 ) . A trend toward improved performance status and reduced consumption of analgesics was also observed . Patients in the 90-mg group had more pronounced bone remineralization as measured by total-body bone mineral density . No significant difference was detectable between the two pamidronate treatments in any of the parameters evaluated . In conclusion , bone pain can be effectively reduced by repeated pami-dronate infusions in patients with advanced osteolytic bone disease .  Pamidronate 90 mg every 3 weeks results in higher bone remineralization , but this difference did not translate into a further increase of palliative effects PURPOSE Bisphosphonates have been found to reduce the incidence of skeletal-related events ( SREs ) in patients with multiple myeloma . This is the first double-blind , r and omized , placebo-controlled study to assess the efficacy of ib and ronate , a third-generation amino-bisphosphonate , in preventing SREs in advanced-stage multiple myeloma patients . PATIENTS AND METHODS Patients with multiple myeloma stage II or III were r and omly assigned to receive either ib and ronate 2 mg or placebo as a monthly intravenous ( IV ) bolus injection for 12 to 24 months in addition to conventional chemotherapy .  SREs such as peripheral pathologic or vertebral fractures , hypercalcemia , severe bone pain , and bone radiotherapy or surgery were analyzed . Bone-turnover markers were also studied . Finally , post hoc analyses of bone morbidity and survival were performed . RESULTS Ninety-nine patients per treatment group were assessable for efficacy analysis . The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups . In overall evaluation , no differences were found between the treatment groups regarding bone pain , analgesic drug use , quality of life , and median survival ( 33.1 v 28.2 months , respectively ) . Explorative post hoc analyses revealed that ib and ronate patients with strongly suppressed bone-turnover markers ( > or = 30 % and > or = 50 % mean reduction of serum osteocalcin and urinary C-terminal telopeptides ) developed significantly less bone morbidity .  Ib and ronate was tolerated well during as many as 25 therapy cycles . CONCLUSION Monthly injections of ib and ronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal‐related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy , 300 patients were included in a r and omized multi‐centre trial . Patients were given oral pamidronate at a dose of 300 mg daily , or placebo , in addition to conventional intermittent melphalan/prednisolone ( and in some cases alpha‐interferon ) treatment . With a median treatment duration of about 550 d , no statisticallly significant reduction in skeletal‐related morbidity ( defined as bone fracture , related surgery , vertebral collapse , or increase in number and /or size of bone lesions ) could be demonstrated . Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia . However , in patients treated with pamidronate there were fewer episodes of severe pain ( P = 0.02 ) and a decreased reduction of body height of 1.5 cm ( P = 0.02 ) . The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general Although osteosclerotic metastases are characteristic of prostatic carcinoma , bone resorption is also accelerated . Since clodronate inhibits bone resorption and relieves bone pain , we have given it to patients with painful bone disease from prostatic cancer after failure of hormonal therapy . All patients received estramustine phosphate orally . Simultaneously they were r and omly allocated to clodronate ( 36 ) and placebo ( 39 ) groups . Clodronate was given by mouth . The dose was 3.2 g for the first month , thereafter 1.6 g. Pain relief was more distinct in the clodronate group where one third of patients were totally free of bone pain . The use of analgesics stopped in 38 % of patients on clodronate and in 18 % on placebo which effect probably belongs to estramustine phosphate . Serum calcium concentration decreased more markedly in the clodronate group .  Clodronate dose of 3.2 g seemed to be more potent than that of 1.6 g. Side effects were uncommon and occurred equally in both groups . No significant differences were seen in median survival or survival rates between the groups Summary In 1989 , a prospect i ve r and omized multicenter study was initiated in order to determine the safety and efficacy of oral clodronate in myeloma patients . The primary objective of this long-term trial is to evaluate whether supportive clodronate is able to prevent or retard the progression of bone disease and reduce the occurrence of characteristic complications : pain , pathologic fractures , and hypercalcemia . We now report first results as an interim analysis , including data obtained from 26 patients ( total number of Tübingen patients n=36 ) who entered the study at theMedizinische Universitätsklinik Tübingen . Patients were r and omized to receive either chemotherapy alone ( melphalan 15 mg/m2 i.v .  on day 1 and prednisolone 60 mg/m2 orally on days 1–4  every 4 weeks ( control group ) or in combination with 1600 mg clodronate/day orally as a single dose for a period of at least 1 year . Repeated radiologic examinations in addition to hematologic and biochemical analysis were performed in order to evaluate the skeletal status with respect to lytic bone lesions and osteoporosis and the course of serum M protein and light chain excretion into urine . Clodronate treatment result ed in a significant decrease of serum calcium concentrations and of biochemical indices for bone resorption . No  clodronate-related toxicity or hypocalcemia was oberved . In patients treated with chemotherapy alone , this effect was less marked and discontinuous . Clodronate-treated patients developed fewer progressive bone lesions ( significant for lytic , not for osteoporotic lesions ) . No hypercalcemic episodes occurred in the clodronate-treated patients , but there were six episodes in the control group . Whereas the number of vertebral fractures was evidently less is clodronate-treated patients , three of those patients suffered from multiple fractures of long bones and ribs . All together , 12 pathologic fractures occurred in five clodronate-treated patients , whereas in the control group 23 pathologic fractures occurred in the same number of patients during the whole observation period . The final analysis of all multicenter included patients should clarify these findings . There was a significant finding that clodronate proved to have an analgesic effect BACKGROUND As previously shown , the combination of st and ard and rogen ablation therapy with somatostatin analog and dexamethasone in metastatic and rogen ablation-refractory ( stage D3 ) prostate cancer ( PrCa ) patients has a favorable profile of side-effects , durable objective antitumor activity ( up to 60 % partial response rate ) and palliative effects .  Bisphosphonates interfere with bone remodeling at the sites of PrCa bone metastases and have been postulated to have indirect and /or direct anti-PrCa activity . MATERIAL S AND METHODS A r and omized controlled clinical trial was conducted to compare a combination of somatostatin analog ( octreotide 20 mg i.m . every 28 days ) and oral dexamethasone ( 4 mg daily for 1 month , gradually reduced to 1 mg daily by the fourth month , with a 1 mg daily maintenance dose thereafter ) plus zoledronate ( 4 mg i.v . every 4 weeks ) vs. zoledronate only . All patients in both arms remained in basic and rogen blockade throughout the study . RESULTS Thirty-eight stage D3 patients ( mean age 72.8 + /- 6.8 years ) were r and omized to either treatment arm of the study . The trial was stopped after a pre-specified interim analysis met the criteria for early closure , i.e. significant difference in outcomes between the two treatment arms . Partial responses ( PR , > or = 50 % PSA decline ) were observed in 13 out of 20 patients with combination therapy vs. none with zoledronate . The combination therapy arm had significantly better outcome with respect to median progression-free survival ( 7.0 vs. 1.0 months , p < 0.0001 ) , median overall survival ( OS ) ( 12.0 vs. 9.0 months , p = 0.0027 ) , median PrCa-specific OS ( defined as time from onset of ther 
    Output:
    
Conclusion : Evidence to support an analgesic role for bisphosphonates and denosumab is weak .
Bisphosphonates and denosumab appear to be beneficial in preventing pain by delaying the onset of bone pain rather than by producing an analgesic effect per se