title: Zoledronic Acid Markedly Improves Bone Mineral Density for Patients with Monoclonal Gammopathy of Undetermined Significance and Bone Loss Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study VTD consolidation, without bisphosphonates, reduces bone resorption and is associated with a very low incidence of skeletal-related events in myeloma patients post ASCT Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. An open‐label, phase 2 trial of denosumab in the treatment of relapsed or plateau‐phase multiple myeloma Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results
abstract: Purpose : Patients with monoclonal gammopathy of undetermined significance ( MGUS ) have increased rates of bone resorption , osteopenia , osteoporosis , and risk of fractures . This study was undertaken to determine the efficacy and safety of zoledronic acid for patients with MGUS and enhanced bone loss . Experimental Design : In this phase II open-label study , 54 patients with MGUS and osteopenia or osteoporosis were administered zoledronic acid 4 mg i.v . at 0 , 6 , and 12 months . The primary efficacy end point was bone mineral density , assessed using a dual-energy X-ray absorptiometry scan in the lumbar (L)-spine done at screening and at 13 months ( 1 month after the final zoledronic acid infusion ) . Results : At study end for all patients ( N = 54 ) , L-spine T-scores improved by a median of + 0.27 ( range , −0.38 to + 3.91 ) , corresponding to a median increase in bone mineral density of + 15.0 % ( range , −18.0 % to + 1,140.0 % ; P < 0.0001 ) . Hip T-scores improved by a median of + 0.10 ( range , −2.40 to + 2.03 ) , corresponding to a median increase of + 6.0 % ( range , −350.0 % to + 165.0 % ) . During the study , no new fractures , osteonecrosis of the jaw , or significant renal adverse events were reported . Conclusions : Zoledronic acid administered i.v . at a dosage of 4 mg every 6 months for three doses total was well-tolerated and substantially improved bone mineral density for patients with MGUS and bone loss .  Zoledronic acid may be effective for the prevention of new fractures in this high-risk population The Medical Research Council Myeloma IX Trial ( IS RCT NG8454111 ) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid ( ZOL ) and oral clodronate ( CLO ) in 1960 patients with newly diagnosed multiple myeloma .  Overall survival ( OS ) and skeletal-related event ( SRE ) data have been reported for the overall trial population . The present analysis investigated optimal therapy regimens for different patient population s in Myeloma IX . Patients were assigned to intensive or nonintensive treatment pathways and r and omized to induction cyclophosphamide , vincristine , doxorubicin , and dexamethasone ( CVAD ) versus cyclophosphamide , thalidomide , and dexamethasone ( CTD ; intensive ) or melphalan and prednisolone versus attenuated oral CTD ( CTDa ; nonintensive ) . Patients were also r and omized to ZOL or CLO . In the nonintensive pathway , CTDa produced better responses and lower SRE rates than melphalan and prednisolone . ZOL improved OS compared with CLO independently of sex , stage , or myeloma subtype , most profoundly in patients with baseline bone disease or other SREs . In patients treated for ≥ 2 years , ZOL improved OS compared with CLO from r and omization ( median not reached for either ; P = .02 ) and also from first on- study disease progression ( median , 34 months for ZOL vs 27 months for CLO ; P = .03 ) . Thalidomide-containing regimens had better efficacy than traditional regimens , and ZOL demonstrated greater benefits than CLO A prospect i ve , multicenter , r and omized trial comparing pamidronate administration ( 60–90 mg once a month for 1 year ) versus simple observation in 177 patients with asymptomatic myeloma was performed to explore whether the administration of this drug reduces the rate of and /or the time to progression to overt , symptomatic disease . No relevant side effects were recorded in pamidronate-treated patients . With a minimum follow-up of 5 years for live patients , there were 56/89 ( 62.9 % ) progressions in the pamidronate-treated group and 55/88 ( 62.5 % ) within the controls ( p = NS ) . Median time to progression was 46 and 48 months , respectively ( p = NS ) . Overall survival was also similar between the two groups . Skeletal-related events at the time of progression were observed in 40/55 ( 72.7 % ) controls , but only in 22/56 ( 39.2 % ) pamidronate-treated patients ( p = 0.009 ) . In conclusion , the administration of pamidronate in asymptomatic myeloma , while reducing bone involvement at progression , did not decrease the risk of transformation and the time to progression into overt myeloma Background Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma . Hence , we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy . Methods Twenty-four patients who were enrolled in a large r and omized trial of thalidomide vs no thalidomide maintenance therapy for myeloma , in which all patients also received zoledronic acid  , were recruited to a pharmacokinetic and renal safety sub- study , and followed for up to 16 months . Results No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients r and omized to thalidomide or not . Conclusion In myeloma patients receiving maintenance therapy , the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone We prospect ively evaluated the effect of bortezomib , thalidomide and dexamethasone ( VTD ) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation ( ASCT ) .  VTD started on day 100 post ASCT ; patients received four cycles of VTD ( first block ) , were followed without treatment for 100 days and then received another four VTD cycles ( second block ) . During this 12-month period , bisphosphonates were not administered . Best response included stringent complete remission ( sCR ) in 15 ( 35.7 % ) patients , complete response ( CR ) in 13 ( 30.9 % ) , vgPR in 7 ( 16.6 % ) , PR in 4 ( 9.5 % ) , while 3 ( 7.1 % ) patients developed a progressive disease ( PD ) . Importantly , 33.3 % and 47.6 % of patients improved their status of response after the first and second VTD block , respectively . VTD consolidation result ed in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I ( CTX ) , soluble receptor activator of the nuclear factor-kappa B lig and ( sRANKL ) and osteocalcin ( OC ) , whereas bone-specific alkaline phosphatase ( bALP ) remained stable compared with pre-VTD values . During the study period , only one patient with a PD developed a skeletal-related event ( that is , radiation to bone ) . The median time to progression ( TTP ) after ASCT was 34 months and the median time of next treatment was 40 months . We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events ( SREs ) despite the absence of bisphosphonates ; the later do not appear to be necessary in this context In a phase 3 trial of denosumab vs zoledronic acid in patients ( n=1776 ) with bone metastases and solid tumors or multiple myeloma , denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events . There was no difference in overall survival between the two groups ; however , an ad hoc overall survival analysis in the multiple myeloma subset of patients ( n=180 ) favored zoledronic acid ( hazard ratio ( HR ) 2.26 ; 95 % confidence interval ( CI ) 1.13–4.50 ; P=0.014 ) . In the present analysis , we found imbalances between the groups with respect to baseline risk characteristics . HRs with two-sided 95 % CIs were estimated using the Cox model . After adjustment in a covariate analysis , the CI crossed unity ( HR 1.86 ; 95 % CI 0.90–3.84 ; P=0.0954 ) . Furthermore , we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group ; after accounting for these , the HR was 1.31 ( 95 % CI 0.80–2.15 ; P=0.278 ) . In conclusion , the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial Summary Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease , and zoledronic acid has shown potential anticancer effects in pre clinical and clinical studies . We aim ed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma . Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK . Computer-generated r and omisation sequence was used to allocate patients equally , via an automated telephone service , to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily . Patients also received intensive or non-intensive induction chemotherapy . No investigators , staff , or patients were masked to treatment allocation , and bisphosphonate and maintenance therapy continued at least until disease progression . The primary endpoints were overall survival , progression-free survival , and overall response rate . We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival , and with logistic regression models for overall response rate . Analysis was by intention to treat . This trial is registered , number IS RCT N68454111 . Findings 1970 patients were enrolled between May , 2003 , and November , 2007 , of whom 1960 were eligible for intention-to-treat analysis : 981 in the zoledronic acid group ( 555 on intensive chemotherapy  , 426 on non-intensive chemotherapy ) ; and 979 on clodronic acid  ( 556 on  intensive chemotherapy , 423 on  non-intensive chemotherapy ) . The treatment cutoff was Oct 5 , 2009 , with patients receiving bisphosphonates for a median of 350 days ( IQR 137–632 ) before disease progression , with a median of 3·7 years ' follow-up ( IQR 2·9–4·7 ) . Zoledronic acid  reduced mortality by 16 % ( 95 % CI 4–26 ) versus clodronic acid ( hazard ratio [ HR ] 0·84 , 95 % CI 0·74–0·96 ; p=0·0118 ) , and extended median overall survival by 5·5 months ( 50·0 months , IQR 21·0 to not reached vs 44·5 months , IQR 16·5 to not reached ; p=0·04 ) . Zoledronic acid also significantly improved progression-free survival by 12 % ( 95 % CI 2–20 ) versus clodronic acid ( HR 0·88 , 95 % CI 0·80–0·98 ; p=0·0179 ) , and increased median progression-free survival by 2·0 months ( 19·5 months , IQR 9·0–38·0 vs 17·5 months , IQR 8·5–34·0 ; p=0·07 ) . Rates of complete , very good partial , or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy ( 432 patients [ 78 % ] vs 422 [ 76 % ] ; p=0·43 ) or non-intensive induction chemotherapy ( 215 [ 50 % ] vs 195 [ 46 % ] ; p=0·18 ) . Both bisphosphonates were generally well tolerated , with similar occurrence of acute renal failure and treatment-emergent serious adverse events , but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw ( 35 [ 4 % ] ) than was clodronic acid ( 3 [ < 1 % ] ) . Interpretation Consistent with the potential anticancer activity of zoledronic acid , overall survival improved independently of prevention of skeletal-related events , showing that zoledronic acid has treatment benefits beyond bone health . These findings support immediate treatment with zoledronic acid  in patients with newly diagnosed multiple myeloma , not only for prevention of skeletal-related events , but also for potential antimyeloma benefits . Funding Medical Research Council ( London , UK ) , with unrestricted educational grants from Novartis , Schering Health Care , Chugai , Pharmion , Celgene , and Ortho Biotech PURPOSE The reported incidence of osteonecrosis of the jaw ( ONJ ) ranges from 0.94 % to 18.6 % . This cohort study aim ed to calculate the incidence of and identify the risk factors for ONJ  in patients with cancer treated with intravenous zoledronate , ib and ronate , and pamidronate .  PATIENTS AND METHODS Data analyzed included age , sex , smoking status , underlying disease , medical and dental history , bisphosphonates ( BP ) type , and doses administered . Relative risks , crude and adjusted odds ratios ( aORs ) , and cumulative hazard ratios for ONJ development were calculated . RESULTS We included 1,621 patients who received 29,006 intravenous doses of BP , given monthly .  Crude ONJ incidence was 8.5 % , 3.1 % , and 4.9 % in patients with multiple myeloma , breast cancer , and prostate cancer , respectively . Patients with breast cancer demonstrated a reduced risk for ONJ development , which turned out to be nonsignificant after adjustment for other variables . Multivariate analysis demonstrated that use of dentures ( aOR = 2.02 ; 95 % CI , 1.03 to 3.96 ) , history of dental extraction ( aOR = 32.97 ; 95 % CI , 18.02 to 60.31 ) , having ever received zoledronate ( aOR = 28.09 ; 95 % CI , 5.74 to 137.43 ) , and each zoledronate dose ( aOR = 2.02 ; 95 % CI , 1.15 to 3.56 ) were associated with increased risk for ONJ development . Smoking , periodontitis , and root canal treatment did not increase risk for ONJ in patients receiving BP .  CONCLUSION The conclusions of this study vali date d dental extraction s and use of dentures as risk factors for ONJ development . Ib and ronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication ; however , r and omized controlled trials are needed to vali date these results . Before initiation of a bisphosphonate , patients should have a comprehensive dental examination . Patients with a challenging dental situation should have dental care attended to before initiation of these drugs RANKL is a key mediator of osteoclast differentiation , activation , and survival . Pre clinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma ( MM ) cells in the bone marrow . Reports have also shown that inhibiting RANKL may have a direct effect on RANK‐expressing myeloma cells and a therapeutic role in treating the disease . In mouse myeloma models , inhibition of RANKL led to reduced serum paraprotein levels and tumor burden . Based on this hypothesis , this proof‐of‐concept , single‐arm study investigated whether RANKL inhibition with denosumab could reduce serum M‐protein levels in relapsed or plateau‐phase myeloma subjects . All subjects received denosumab monthly , with loading doses on days 8 and 15 of month one , until disease progression or subject discontinuation . Results of this ongoing study demonstrated that no subjects in either cohort met the protocol ‐defined objective response criteria of complete response ( CR ) or partial response ( PR ) , but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates , as evidence d by suppressed levels of the bone turnover marker , serum C‐terminal telopeptide of type 1 collagen ( sCTx ) . Eleven ( 21 % ) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months . Nineteen ( 46 % ) subjects with plateau‐phase myeloma maintained stable disease for up to 18.3 months . The adverse event ( AE ) profile for denosumab and its dosing schedule in these population s was consistent with that for advanced cancer patients receiving systemic therapy . Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau‐phase MM are warranted . Am . J. Hematol . 2009 . © 2009 Wiley‐Liss , This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse . One hundred patients were r and omized to receive either zoledronic acid ( 4 mg iv/4 weeks , 12 doses ) ( n=51 ) or not ( n=49 ) . Experimental and control groups were well balanced for disease and prognostic features . Zoledronic acid did not show an antitumor effect according to changes in M-component . However , there were fewer symptomatic progressions in the experimental group than in the control group ( 34 versus 41 , respectively ; P=0.05 ) result ing in a median time to symptoms of 16 versus 10 months ( P=0.161 ) . The median time to next therapy was also slightly longer for the treated group than the untreated , control group ( 13.4 versus 10.1 months ) , although the difference was not statistically significant ( P=0.360 ) . The pattern of relapses was different for treated versus control patients : progressive bone disease ( 8 versus 20 ) , anemia ( 24 versus 18 ) , renal dysfunction ( 1 versus 2 ) , and plasmacytomas ( 1 versus 1 , respectively ) . This concurred with fewer skeletal-related events in the treated group than in the control group ( 2 versus 14 ) , with a projected 4-year event proportion of 6 % versus 40 % ( P<0.001 ) . In summary , zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma , but does reduce the risk of progression with symptomatic bone disease and skeletal complications . This trial was registered in the Clinical Trials.gov data base with code BACKGROUND Compared with placebo , prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma . However , because of toxicity associated with long-term bisphosphonate treatment , establishing the lowest effective dose is important . This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma . METHODS This double-blind , r and omised , phase 3 trial was undertaken at 37 clinics in Denmark , Norway , and Sweden . Patients with multiple myeloma who were starting antimyeloma treatment were r and omly assigned in a 1:1 ratio to receive one of two doses of pamidronate ( 30 mg or 90 mg ) given by intravenous infusion once a month for at least 3 years . R and omisation was done by use of a central , computerised minimisation system . Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer ( EORTC ) QLQ-C30 question naire ( scale 0 - 100 ) . All patients who returned question naires at 12 months and were still on study treatment were included in the analysis of the primary endpoint . This study is registered with Clinical Trials.gov , number NCT00376883 . FINDINGS From January , 2001 , until August , 2005 , 504 patients were r and omly assigned to  pamidronate 30 mg or 90 mg ( 252 in each group ) . 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis  . Mean physical function at 12 months was 66 points ( 95 % CI 62·9 - 70·0 ) in the 90 mg group and 68 points ( 64·6 - 71·4 ) in the 30 mg group ( 95 % CI of difference -6·6 to 3·3 ; p=0·52 ) . Median time to first skeletal-related event in patients who had such an event was 9·2 months ( 8·1 - 10·7 ) in the 90 mg group and 10·2 months ( 7·3 - 14·0 ) in the 30 mg group ( p=0·63 ) . In a retrospective analysis , eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group . INTERPRETATION Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma . FUNDING Nordic Cancer Union and Novartis Healthcare PURPOSE To evaluate the natural history of bisphosphonate-related  osteonecrosis of the jaw ( ONJ ) in patients with multiple myeloma . PATIENTS AND METHODS Ninety-seven patients with myeloma from the United States ( n = 37 ) and Greece ( n = 60 ) were observed prospect ively for a minimum 3.2 years after ONJ . Patients characteristics were similar with regard to age , bisphosphonate use , and myeloma therapy , except more autologous transplantations were performed on patients in the United States than in Greece ( 73 % v 28 % ; P < .0001 ) . RESULTS ONJ resolved in 60 patients ( 62 % ) , resolved and recurred in 12 patients ( 12 % ) , and did not heal in 25 patients ( 26 % ) . Dental procedures preceded ONJ in 46 patients ( 47 % ) and were more common in those with single episodes ( 35 of 60 , 58 % ) than recurrent or nonhealing ( 11 of 37 , 30 % ; P = .007 ) . Recurrent ONJ followed reinitiation of bisphosphonates in six of 12 patients . Greek patients had more bone pain than United States patients ( 60 % v 30 % , P = .001 ) and were less likely to restart bisphosphonates ( 5 % v 35 % , P < .0002 ) . Myeloma relapses were more common in patients with recurrent/nonhealing than single-episode ONJ ( 84 % v 62 % ; P = .02 ) . Median overall survival from myeloma diagnosis was 10.8 years ( 95 % CI ; 9.3 years to not reached ) and did not differ between patients with single , recurrent , and nonhealing ONJ ( P = .2 ) . CONCLUSION ONJ healed in 75 % of patients . Patients with spontaneous ONJ have a higher risk of nonhealing and recurrence . Reinitiating bisphosphonates after healing of ONJ is a reasonable option in patients experiencing relapse who are at risk of skeletal complications . Further studies of the pathogenesis and healing of ONJ are needed OBJECTIVES Bone disease is a key presenting feature of myeloma . This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone ( VMP ) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase ( ALP ) , a marker for osteoblast activation , and serum Dickkopf-1 ( DKK-1 ) , an inhibitor of osteoblast differentiation , during treatment . METHODS Patients received nine 6-wk cycles of VMP ( bortezomib 1.3 mg/m(2 ) , days 1 , 4 , 8 , 11 , 22 , 25 , 29 , 32 , cycles 1 - 4 , days 1 , 8 , 22 , 29 , cycles 5 - 9 , plus melphalan 9mg/m(2 ) and prednisone 60mg/m(2 ) , days 1 - 4 , cycles 1 - 9 ; N=344 ) or MP alone ( N=338 ) . RESULTS Rates of bisphosphonates use during treatment ( 73 % vs. 82 % ) , progression because of worsening bone disease ( 3 % vs. 11 % ) , and requirement for subsequent radiotherapy ( 3 % vs. 8 % ) were lower with VMP vs. MP . Median maximum ALP increase was significantly higher with VMP vs. MP overall ( 49.7 % vs. 30.3 % , P=0.029 ) , and higher by response group ( complete response [ CR ] : 68.7 % vs. 43.9 % ; partial response [ PR ] : 41.5 % vs. 31.2 % ) . Greater maximum ALP increase was strongly associated with achievement of CR ( P≤0.0001 ) and CR/PR ( P≤0.01 ) . Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 ( P=0.0069 ) . Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients , who achieved best responses of three CR , one PR , and two stable disease . CONCLUSIONS These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma Bisphosphonates ( BPs ) are effective in the prevention and treatment of skeletal‐related events ( SREs ) in patients with symptomatic myeloma who are receiving chemotherapy . Recent data also suggest a possible antineoplastic activity of BPs . Few studies published to date have explored the role of BPs in patients with untreated , asymptomatic myeloma ( AM ) . No data are available on the efficacy of zoledronic acid in these patients Bisphosphonates are recommended in patients with osteolytic lesions secondary to multiple myeloma . We report on the safety of bisphosphonate therapy with long‐term follow‐up in the Medical Research Council Myeloma IX study . Patients with newly diagnosed multiple myeloma were r and omised to zoledronic acid ( ZOL ; 4 mg intravenously every 21–28 d ) or clodronate ( CLO ; 1600 mg/d orally ) plus chemotherapy . Among 1960 patients ( 5·9‐year median follow‐up ) , both bisphosphonates were well tolerated . Acute renal failure events were similar between groups ( ZOL 5·2 % vs. CLO 5·8 % at 2 years ; incidence plateaued thereafter ) . The overall incidence of confirmed osteonecrosis of the jaw ( ONJ ) was low , but higher with ZOL ( ZOL 3·7 % vs. CLO 0·5 % ; P < 0·0001 ) . ONJ events were generally low grade and most occurred between 8 and 30 months ( median time to ONJ , 23·7 months ) . Among 10 patients with ONJ recovery data , four patients in the ZOL  group completely recovered , two patients improved , and three patients experienced no improvement ; one CLO patient experienced no improvement . Dental surgery or trauma preceded ONJ in six ZOL patients . The incidence of renal adverse events was similar for ZOL and  CLO . ONJ incidence remained low and was lower with CLO compared to ZOL . We have seen no further ONJ cases to date
target: Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative .
  Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting .
background: Purpose To up date guideline recommendations on the role of bone-modifying agents in multiple myeloma .