Bisphosphonates are analogs of pyrophosphate. They bind to calcium and bone hydroxyapatite, and they inhibit osteoclast function.

All patients with MM should be treated with monthly IV bisphosphonates to reduce pain, treat osteoporosis, and prevent skeletal complications (hypercalcemia, pathologic fractures, spinal cord compression).

1) Zoledronic acid (Zometa ®), given as a 15-minutes infusion of 4 mg
2) Pamidronate (Aredia ®), given as a single 2-hour infusion of 30-90 mg

In patients with osteopenia or osteoporosis documented at the DEXA scan, the addition of calcium 600 mg/day and vitamin D3 400 IU/day is recommended.

Bisphosphonate therapy in myeloma can lead to several toxicities, including:
  - Flu-like symptoms (e.g., fever, fatigue, body aches)
  - Renal insufficiency
  - Osteonecrosis of the jaw (ONJ)
  - Atypical fractures of the femur

Dental evaluation before starting IV bisphosphonate therapy is advised.

The optimal duration of bisphosphonate therapy has not been defined. Since the risk of ONJ increases after 2 years of therapy, treatment with bisphosphonates can be stopped after 2 years, in case the myeloma is in a deep remission. It can be resumed if new skeletal-related events develop.


American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma.
J Clin Oncol. 2007 Jun 10;25(17):2464-72.
Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, Orlowski RZ, Roodman DG, Twilde P, Anderson K; American Society of Clinical Oncology.
These 2007 ASCO guidelines recommend the use of either zoledronic acid 4 mg IV over at least 15 minutes or pamidronate 90 mg IV over at least 2 hours every 3-4 weeks for patients with multiple myeloma who have lytic bone lesions or spine compression fractures from osteopenia. The guidelines indicate dose modifications for those patients with renal insufficiency. Bisphosphonate treatment should be continued for a period of 2 years. After 2 years, physicians should consider to discontinue the use of bisphosphonates, particularly in patients with responsive or stable disease.

Comparative effectiveness on survival of zoledronic acid versus pamidronate in multiple myeloma.
Leuk Lymphoma. 2015 Mar;56(3):615-21.
Sanfilippo KM, Gage B, Luo S, Weilbaecher K, Tomasson M, Vij R, Colditz G, Carson K.
This study is a retrospective comparison of pamidronate vs zoledronic acid in 1018 patients with multiple myeloma. Median follow-up was 27 months. The authors believe that zoledronic acid should be the preferred bisphosphonate for patients with multiple myeloma, because it was associated with a 25% reduction in skeletal-related events, and a 22% reduction in risk of death compared to pamidronate.




Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma.
Br J Haematol. 2002 Nov;119(2):475-83.
Gordon S, Helfrich MH, Sati HI, Greaves M, Ralston SH, Culligan DJ, Soutar RL, Rogers MJ.
In this study, a single infusion of pamidronate induced apoptosis of human plasma cells in 16 patients with newly diagnosed multiple myeloma. The results suggest that pamidronate may have direct and/or indirect anti-tumour effects in patients with multiple myeloma.

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.
Lancet Oncol. 2010 Oct;11(10):973-82.
Gimsing P, Carlson K, Turesson I, Fayers P, Waage A, Vangsted A, Mylin A, Gluud C, Juliusson G, Gregersen H, Hjorth-Hansen H, Nesthus I, Dahl IM, Westin J, Nielsen JL, Knudsen LM, Ahlberg L, Hjorth M, Abildgaard N, Andersen NF, Linder O, Wisløff F.
This is a double-blind randomised study of 504 myeloma patients, comparing two doses of pamidronate -30 mg or 90 mg- given IV monthly for at least 3 years. Results:
  - Median time to first skeletal-related event was 9.2 months with 90 mg and 10.2 months with 30 mg (p= 0.63)
  - Osteonecrosis of the jaw developed in 8 patients with 90 mg and 2 patients with 30 mg
The authors recommended that 30 mg is the optimal dose for prevention of bone disease in patients with multiple myeloma.



Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival.
J Bone Miner Res. 2003 Mar;18(3):482-92.
Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K.
This study investigated the effect of zoledronic acid on the development of bone disease, tumor burden, and disease-free survival in C57BL/KaLwRij mice injected with 5T2MM murine myeloma cells. After 8 weeks, a paraprotein was detected in all animals. All mice injected with tumor cells developed osteolytic lesions, a decrease in bone formation, and a decrease in bone mineral density. After treatment with zoledronic acid 120 mcg/kg subcutaneously twice a week, authors observed reduced development of osteolytic bone disease, decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. Kaplan-Meier survival analysis demonstrated an increased survival after treatment with zoledronic acid when compared with controls. Therefore, zoledronic acid can prevent the development of osteolytic bone disease, decrease tumor burden, and increase survival in a murine model of multiple myeloma.

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.
Cancer. 2003 Oct 15;98(8):1735-44.
Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein MA, Coleman RE, Reitsma DJ, Chen BL, Seaman JJ.
This study compared the safety and efficacy of long-term treatment (25 months) with zoledronic acid or pamidronate in 1648 patients with bone lesions secondary to multiple myeloma orr advanced breast cancer. Patients were randomized to receive zoledronic acid 4-8 mg IV over 15 minutes or pamidronate 90 mg IV over 2 hours every 3-4 weeks for 24 months. Endpoints were the proportion of patients with skeletal-related events and hypercalcemia of malignancy. After 25 months of follow-up, zoledronic acid reduced the proportion of patients with an SRE and skeletal morbidity similar to pamidronate. Compared with pamidronate, zoledronic acid reduced the risk of developing skeletal complications by an additional 16%. In patients with breast carcinoma, zoledronic acid appeared to be more effective than pamidronate, and it reduced the risk of SREs by an additional 20% compared with pamidronate. Zoledronic acid and pamidronate were tolerated equally well, and the most common toxicities were nausea, fatigue, and bone pain. The authors conclude that zoledronic acid and pamidronate have a similar efficacy in patients with multiple myeloma, and that zoledronic acid is more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast cancer.

The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane.
Eur J Haematol. 2005 Jun;74(6):496-500.
Avcu F, Ural AU, Yilmaz MI, Ozcan A, Ide T, Kurt B, Yalcin A.
This study investigated the effect of zoledronic acid on the development of pristane-induced plasmacytoma in BALB/c mice. Authors found a a significant difference in survival between the group of mice treated with pristane alone and the group receiving pristane + xoledronic acid. The increased survival indicates a direct anti-tumor effect of zoledronic acid in the development of pristane-induced plasmacytomas in BALB/c mice. This hypothesis should now be further investigated in clinical trials.

The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation.
Int J Cancer. 2010 Jan 1;126(1):239-46.
Guenther A, Gordon S, Tiemann M, Burger R, Bakker F, Green JR, Baum W, Roelofs AJ, Rogers MJ, Gramatzki M.

This study demonstrated that zoledronic acid has a direct antitumor effect, because its administration in a plasmacytoma xenograft model without skeletal lesions resulted in prolongation of survival in SCID mice.

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.
Lancet. 2010 Dec 11;376(9757):1989-99.
Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group.
1970 patients with myeloma were randomized to zoledronic acid 4 mg IV every 3-4 weeks (981 patients) or clodronic acid 1600 mg PO qd (979 patients), continued at least until disease progression. After a median of 3.7 years of follow-up, skeletal-related events were lower in the group treated with zoledronic acid (27% vs 35%). ONJ was observed in 4% of patients treated with zoledronic acid, and <1% of patients treated with clodronic acid. Response rates were equivalent in the two groups, but median overall survival was longer in the group treated with zoledronic acid (50 vs 44.5 months, p= 0.04), regardless of the type of chemotherapy given. Improvement of overall survival with zoledronic acid was independent of its prevention of skeletal-related events. The median duration of zoledronic acid therapy in this study was only 1 year.

A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma.
Leukemia. 2013 Jan;27(1):220-5.
Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV.
In this randomized study of zoledronic acid (33 patients) vs zoledronic acid + thalidomide (35 patients) in smoldering myeloma, zoledronic acid alone did not produce anti-tumor responses.

Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z-MARK Study.
Clin Cancer Res. 2016 Mar 15;22(6):1378-84.
Raje N, Vescio R, Montgomery CW, Badros A, Munshi N, Orlowski R, Hadala JT, Warsi G, Argonza-Aviles E, Ericson SG, Anderson KC.
This is a prospective study conducted in 67 centers in the U.S. Patients received zoledronic acid either monthly or every 3 months, based on the urine levels of the N-telopeptide of type 1 collagen (uNTX), a bone turnover marker. If levels were high (>50 mmol/mmol creatinine), consistent with increased bone resorption, zoledronic acid was given every 4 weeks, if levels were low (<50) every 12 weeks. Only 6% of patients developed a skeletal-related event, despite the fact that the vast majority of patients received zoledronic acid every 12 weeks. No major toxicities were observed. ONJ incidence was 3.3% beyond 3 years.

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.
JAMA. 2017 Jan 3;317(1):48-58.
Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, Qin R, Go RS, Grubbs SS, O'Connor T, Velasco MR Jr, Weckstein D, O'Mara A, Loprinzi CL, Shapiro CL.
This is a randomized study of zoledronic acid in 1822 patients with cancer involving the bones. Among them, 278 patients had multiple myeloma. Patients were randomized into 2 groups: one (911 patients) received zoledronic acid, at standard schedule, i.e., once a month, and the other (911 patients) received zoledronic acid every 3 months. Treatment was continued for 2 years (= 24 vs 8 doses). The clinical outcomes (skeletal-related events) of the longer dosing interval were similar to those of the monthly infusions.  

Prolonged Use of Zoledronic Acid (4 Years) Did Not Improve Outcome in Multiple Myeloma Patients.
Clin Lymphoma Myeloma Leuk. 2017 Apr;17(4):207-210.
Avilès A, Nambo MJ, Huerta-Guzmàn J, Cleto S, Neri N.
A total of 170 patients with newly diagnosed myeloma were divided in two groups, one treated with zoledronic acid for 2 years (standard group), and the other for 4 years. Overall survival at 5 years was the same (68% in both groups), but the rate of skeletal events was reduced (21% in the 2-year group, and 43% in the 4-year group (p<0.001).



Effect of daily etidronate on the osteolysis of multiple myeloma.
J Clin Oncol. 1991 Aug;9(8):1397-402.
Belch AR, Bergsagel DE, Wilson K, O'Reilly S, Wilson J, Sutton D, Pater J, Johnston D, Zee B.
This study showed that oral etidronate is ineffective in MM.

Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma.
J Clin Oncol. 2002 May 1;20(9):2353-9.
Menssen HD, Sakalová A, Fontana A, Herrmann Z, Boewer C, Facon T, Lichinitser MR, Singer CR, Euller-Ziegler L, Wetterwald M, Fiere D, Hrubisko M, Thiel E, Delmas PD.
Ibandronate is a third-generation amino-bisphosphonate. This is a double-blind, randomized, placebo-controlled study that assesses the efficacy of ibandronate in preventing skeletal-related events (SREs) in patients with advanced myeloma. Patients were randomly assigned to receive either ibandronate 2 mg or placebo IV monthly for 12-24 months. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the groups, and the authors concluded that ibandronate 2 mg IV monthly neither reduced bone morbidity nor prolonged survival in patients with multiple myeloma.



Pamidronate induces bone formation in patients with smouldering or indolent myeloma, with no significant anti-tumour effect.
Br J Haematol. 2002 Jul;118(1):239-42.
Martín A, García-Sanz R, Hernández J, Bladé J, Suquía B, Fernández-Calvo J, González M, Mateo G, Orfao A, San Miguel JF.
In this study, 12 patients with smoldering or indolent myeloma received 12 courses of IV pamidronate as a single agent to evaluate both the antitumour and bone metabolism effects.
Disease response among 12 patients:
 - 1 patient had minor response
 - 8 patients had stable disease
 - 3 patients had disease progression
Bone density significantly increased. The results of this study suggest that pamidronate treatment reduces bone turnover in smoldering or indolent MM, but it has no significant antitumor effect.

Pamidronate for early-stage, untreated myeloma.
J Clin Oncol. 2003 Aug 15;21(16):3177-8.
Musto P, Falcone A, Sanpaolo G, Bodenizza C, Carella AM.
43 patients with asymptomatic myeloma, either smoldering or stage IA, were treated with pamidronate 60-90 mg IV monthly for 1 year and every 3 months thereafter, until progression. No responses were seen. Progression-free survival was not improved, because time to progression was similar to that in a control group (19 months in both the pamidronate group and control group).

A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma.
Cancer. 2008 Oct 1;113(7):1588-95.
Musto P, Petrucci MT, Bringhen S, Guglielmelli T, Caravita T, Bongarzoni V, Andriani A, D'Arena G, Balleari E, Pietrantuono G, Boccadoro M, Palumbo A; GIMEMA (Italian Group for Adult Hematologic Diseases)/Multiple Myeloma Working Party and the Italian Myeloma Network.
163 patients with asymptomatic myeloma were randomized to receive either zoledronic acid 4 mg IV monthly x12 (81 patients) or observation (82 patients). Progression to symptomatic myeloma was similar in the two groups: 44.4% of patients in the zoledronic acid group and 45.1% of the patients in the control group. The median time to progression was also similar (67 vs 59 months, p= 0.8312). At progression, the skeletal complications were reduced in the zoledronic acid group (55.5% vs 78.3%, p= 0.041)ONJ was seen in 1 patient. This study demonstrated that zoledronic acid reduced the development of skeletal complications, but it did not reduce/delay the progression of the disease. The results do not support the notion that bisphosphonate may have a direct antineoplastic activity.

Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study.
Leuk Lymphoma. 2011 May;52(5):771-5.
D'Arena G, Gobbi PG, Broglia C, Sacchi S, Quarta G, Baldini L, Iannitto E, Falcone A, Guariglia R, Pietrantuono G, Villani O, Martorelli MC, Mansueto G, Sanpaolo G, Cascavilla N, Musto P; Gimema (Gruppo Italiano Malattie Ematologiche Dell'Adulto); Multiple Myeloma Working Party; Gisl (Gruppo Italiano Studio Linfomi) Cooperative Group.
177 patients with asymptomatic myeloma were randomized to pamidronate vs observation. After a minimum follow-up of 5 years, pamidronate reduced the skeletal-related events at progression (39% vs 72%), but neither EFS (46 vs 48 months, NS) nor overall survival were improved.



Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial.
Haematologica. 2015 Sep;100(9):1207-13.
García-Sanz R, Oriol A, Moreno MJ, de la Rubia J, Payer AR, Hernández MT, Palomera L, Teruel AI, Blanchard MJ, Gironella M, Ribas P, Bargay J, Abellá E, Granell M, Ocio EM, Ribera JM, San Miguel JF, Mateos MV; Spanish Myeloma Group (GEM/PETHEMA).
In this study, 100 patients with multiple myeloma in relapse were randomized to receive either zoledronic acid 4 mg IV monthly (51 patients) or not (49 patients). Of note, patients had a biochemical relapse (as opposed to symptomatic relapse). The treatment with zoledronic acid did not have any antitumor effect (assessed by measuring the M component), but it was beneficial because it reduced the risk of progression to skeletal-related events (2 vs 14). Median time to symptoms was 16 vs 10 months, but the difference was not statistically significant (p=0.16).





Main toxicities of IV bisphosphonates:
 - Acute phase reactions
 - Hypocalcemia
 - Nephrotoxicity
 - Osteonecrosis of the jaw
 - Atypical fractures



They manifest with fever, myalgias, arthralgias. They are most common after the first infusion, and they usually last 1-3 days.



Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid.
Intern Med J. 2008 Aug;38(8):635-7.
Chennuru S, Koduri J, Baumann MA.
This study reviews the data from 120 patients who received a total of 546 infusions of zoledronic acid. Hypocalcemia developed after 55 infusions (10%) in 42 patients (35%). Symptomatic hypocalcaemia requiring IV replacement occurred in 10 patients (8%). All patients with hypocalcemia had hypomagnesaemia as well. Therefore, hypocalcemia is a common side effect of zoledronic acid. Hypomagnesemia may increase the risk of symptomatic hypocalcemia by blunting the compensatory increase in PTH secretion.



IV bisphosphonates are not recommended for patients with CrCl < 30 mL/min.

Nephrotic proteinuria associated with high-dose pamidronate in multiple myeloma.
Br J Haematol. 2002 Nov;119(2):496-9.
Desikan R, Veksler Y, Raza S, Stokes B, Sabir T, Li ZJ, Jagannath S.
This study reports 5 cases of multiple myeloma who developed nephrotic proteinuria (range: 4-24 g/24 hours) after treatment with pamidronate at increased doses or frequency of administration. After dose reduction or discontinuation of pamidronate, proteinuria returned to normal levels (<1 g/24 hours) in 3 patients, and it decreased from 24 to to 4.5 g/24 hours in 1 patient. Renal biopsies, obtained in 2 patients, showed findings consistent with focal segmental glomerulosclerosis.

Toxic acute tubular necrosis following treatment with zoledronate (Zometa).
Kidney Int. 2003 Jul;64(1):281-9.
Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D'Agati VD.
This study is the first clinical-pathologic report of nephrotoxicity associated with zoledronic acid. Authors report 6 patients (5 patients with multiple myeloma and 1 patient with Paget's disease) who received zoledronate at a dose of 4 mg intravenously over at least 15 minutes once a month for 3-9 months (mean 4.7 months). These patients developed acute renal failure with a serum creatinine increased from a mean baseline level of 1.4 mg/dL to 3.4 mg/dL. Renal biopsy revealed acute tubular necrosis (ATN), and the pathology showed tubular cell degeneration, loss of brush border, and apoptosis. After discontinuation of zoledronic acid, all 6 patients had an improvement in renal function (mean final serum creatinine, 2.3 mg/dL), after 1-4 months of follow-up.



Giampaolo Talamo, M.D.