BISPHOSPHONATES: TOXICITIES

 

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

 

ACUTE PHASE REACTION

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

 

HYPOCALCEMIA

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.

 

NEPHROTOXICITY

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.

 

OSTEONECROSIS OF THE JAW (ONJ)

ONJ is a complication of therapy with pamidronate and zoledronic acid. The most important risk factors for ONJ are:
  - Length of exposure to bisphosphonates
  - History of dental procedures
  - Use of zoledronic acid
The nonexposed variant of ONJ consists of osteonecrosis without bone exposure through an opening in the mucosa. It may manifest with jaw pain, bone enlargement, gingival swelling, and sinus tract.

Some experts recommend holding bisphosphonates for 3 months before and after invasive dental procedures (e.g., tooth extractions and dental implants). There is no need to hold bisphosphonates for root canals.
Antibiotic prophylaxis during dental procedures may help preventing the development of ONJ.

 

Picture of ONJ involving the right mandible (my personal archive):

 

 

 

This is a CT scan (with 3D reconstruction) of a patient with ONJ of the left mandible (my personal archive). There is erosion along the left mandibular canine and premolar teeth:

 

 

 

 

Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.
J Clin Oncol. 2005 Dec 1;23(34):8580-7.
Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA.
This is a prospective study of ONJ in 252 patients who received bisphosphonates. 17 patients (7%) developed ONJ: 11 of 111 (10%) with multiple myeloma, 2 of 70 (3%) with breast cancer, 3 of 46 (6.5%) with prostate cancer, and 1 of 25 (4%) with other neoplasms. The median number of treatment cycles and time of exposure to bisphosphonates were:
  - 35 infusions and 39 months for patients with ONJ
  - 15 infusions and 19 months for patients with no ONJ (p<0.001)
The incidence of ONJ increased with time to exposure:
  - 1.5% among patients treated for 4-12 months
  - 7.7% among patients treated for 37-48 months.
The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate. All but 2 patients with ONJ had a history of dental procedures within the last year or use of dentures. Based on the results, the authors conclude that the length of exposure is the most important risk factor for ONJ, that the type of bisphosphonate plays a role, and that previous dental procedures are a precipitating factor.

Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors.
J Clin Oncol. 2006 Feb 20;24(6):945-52.
Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T.
This is a retrospective review of 90 MM patients who had dental assessments, including 22 patients with ONJ. 27 patients had recent dental extraction, including 12 patients in the ONJ group. Median time from MM diagnosis to ONJ was 8.4 years. ONJ usually presented with pain, and it occurred posterior to the cuspids (n = 20) mostly in the mandible. 4 patients had recurrent ONJ. Bone histology revealed necrosis and osteomyelitis. Microbiology showed actinomycetes (n = 7) and mixed bacteria (n = 9). Risk factors for ONJ were dental extractions, long-term treatment with bisphosphonates, prolonged survival, and older age.

Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis.
J Oral Pathol Med. 2006 Mar;35(3):155-60.
Hansen T, Kunkel M, Weber A, James Kirkpatrick C.
This study examined the histologic findings of 8 cases (5 patients with MM) of ONJ after bisphosphonate treatment. 5 patients had mandibular involvement, and 3 patients had maxillar involvement. Histological analysis revealed diffuse and patchy areas of necrosis of the bone, and all cases were found to have Actinomyces attached to the necrotic bone tissue. In 5 cases, numerous osteoclasts were found close to vital bone, exhibiting signs of bone resorption. Pseudoepitheliomatous hyperplasia was revealed in 5 patients. The authors conclude that Actinomyces are involved in the chronic, non-healing inflammatory process, and believe that both Actinomyces infection and increased osteoclast numbersare involved in the osteolysis of ONJ.

Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients.
Br J Haematol. 2006 Sep;134(6):620-3.
Zervas K, Verrou E, Teleioudis Z, Vahtsevanos K, Banti A, Mihou D, Krikelis D, Terpos E.
This study  evaluated ONJ in 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Number of bisphosphonate infusions increased the risk for ONJ. Zoledronic acid was 10 times more likely to induce ONJ than pamidronate, and ONJ developed earlier with the use of zoledronic acid. Based on the data, the authors conclude that administration of zoledronic acid for more than 2 years requires caution.

Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients - May 2006.
Crit Rev Oncol Hematol. 2007 May;62(2):148-52.
Weitzman R, Sauter N, Eriksen EF, Tarassoff PG, Lacerna LV, Dias R, Altmeyer A, Csermak-Renner K, McGrath L, Lantwicki L, Hohneker JA.
[Review]
An international advisory board of experts provided the following recommendations:
  - Encourage patients to practice good oral hygiene and minimize possible jaw trauma
  - Encourage patients to receive a dental examination prior to initiating bisphosphonate therapy
  - Complete any necessary dental procedures, such as tooth extractions, prior to initiating bisphosphonate therapy
  - Patients should avoid dental surgery during treatment with bisphosphonates
  - Patients should receive regular dental visits during bisphosphonate therapy
  - Refer patients to a dental professional immediately if ONJ is suspected (exposed bone in the oral cavity)

A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma.
Leukemia. 2007 Jul;21(7):1545-8.
Corso A, Varettoni M, Zappasodi P, Klersy C, Mangiacavalli S, Pica G, Lazzarino M.
This study evaluated the incidences of ONJ and skeletal-related events (SREs) in 106 patients with multiple myeloma divided in two groups:
  - Group A (standard schedule of administration): 51 patients who received monthly administrations of bisphosphonates until tolerated
  - Group B (reduced schedule of administration): 55 patients who received monthly administrations of bisphosphonates during the first year, and then every 3 months
Results:
  - The incidence of SREs was similar: 15.1 per 100 person years in group A and 17.7 in group B.
  - The risk of ONJ was lower with the reduced schedule: ONJ developed in 7 patients: 6 in group A and 1 in group B (P=0.049).
  - ONJ developed in patients treated with zoledronic acid, and no ONJ was seen in patients treated only with pamidronate.
These authors conclude that a reduced schedule of zoledronic acid is safer than the standard schedule and, at the same time, it maintains its efficacy in preventing SREs.

Natural history of osteonecrosis of the jaw in patients with multiple myeloma.
J Clin Oncol. 2008 Dec 20;26(36):5904-9.
Badros A, Terpos E, Katodritou E, Goloubeva O, Kastritis E, Verrou E, Zervas K, Baer MR, Meiller T, Dimopoulos MA.
In this study, 97 MM patients with ONJ were observed prospectively for at least 3 years after ONJ. Results:
 - ONJ resolved in 60 patients (62%)
 - ONJ resolved and recurred in 12 patients (12%)
 - ONJ did not heal in 25 patients (26%)
Recurrent ONJ followed reinitiation of bisphosphonates in 6 of 12 patients.

Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series.
Am J Med. 2010 Nov;123(11):1060-4.
Fedele S, Porter SR, D'Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G, Yarom N.
This is a case series of 96 patients with the nonexposed variant of ONJ, i.e., osteonecrosis without bone exposure through an opening in the mucosa.
Clinical features were:
  - Jaw pain (92%)
  - Sinus tract (51%)
  - Bone enlargement (36%)
  - Gingival swelling (18%)
Nonexposed ONJ progressed to bone exposure in 53% of cases, after a mean period of 4.6 months.

 

Osteonecrosis can rarely involve the temporal bone.

Bisphosphonate-associated osteonecrosis of the external auditory canal.
J Laryngol Otol. 2013 May 15:1-3.
Wickham N, Crawford A, Carney AS, Goss AN.

 

Antibiotic prophylaxis has a protective effect.

Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates.
Leuk Lymphoma. 2008 Nov;49(11):2156-62.
Montefusco V, Gay F, Spina F, Miceli R, Maniezzo M, Teresa Ambrosini M, Farina L, Piva S, Palumbo A, Boccadoro M, Corradini P.
This retrospective analysis of 178 patients with MM showed that antibiotic prophylaxis before dental procedures may prevent ONJ. 75 patients received at least one dental procedure, and 43 patients received antibiotic prophylaxis. 9 patients developed ONJ. Only 1 case of ONJ was not correlated with dental procedures. Interestingly, all 8 cases of ONJ observed with dental procedures occurred in the group of patients without antibiotic prophylaxis.

 

Pentoxifylline and tocoferol may have a beneficial effect, according to some experts.

Pentoxifylline and tocopherol in the management of cancer patients with medication-related osteonecrosis of the jaw: an observational retrospective study of initial case series.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Oct;122(4):455-9.
Owosho AA, Estilo CL, Huryn JM, Yom SK.

 

 


 

OTHER

 

DENOSUMAB

Denosumab is a fully human IgG2 monoclonal antibody that binds to RANKL. It acts as a decoy receptor for RANKL. It inhibits osteoclast maturation and function.
Advantages:
  - It is administered SC
  - It can be administered in patients with decreased creatinine clearance
  - It is well tolerated.
    Low risk of acute reactions in the days after treatment
    The incidence of ONJ with denosumab is similar to that observed with zoledronic acid

An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma.
Am J Hematol. 2009 Oct;84(10):650-6.
Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, Smith J, Qian Y, Yeh H, Jun S.
Denosumab was administered in patients with myeloma, either relapsed or in a plateau phase. No CR and no PR were observed in this phase II trial.

Randomized, double-blind study of denosumab versus zoledronic Acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
J Clin Oncol. 2011 Mar 20;29(9):1125-32.
Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H.
This study randomized patients to receive either zoledronic acid 4 mg IV or denosumab 120 mg SC for bone metastases. It included patients with multiple myeloma: 93 in the zoledronic acid arm, and 87 in the denosumab arm. For the entire study population, the median time to development of a skeletal-related event was 16.3 months with zoledronic acid and 20.6 with denosumab. No difference in progression-free survival or overall survival was observed, but a more favorable survival was observed in patients with multiple myeloma receiving zoledronic acid (HR: 2.26, 95% CI: 1.13-4.5). Osteonecrosis of the jaw occurred rarely in both groups (about 1%).

 

GALLIUM NITRATE

Extended survival in advanced-stage multiple myeloma patients treated with gallium nitrate.
Leuk Lymphoma. 2002 Mar;43(3):603-5.
Niesvizkya R, Choy CG, Siegel D, Lyons L, Michaeli J.
This study identified a group of patients with remarkably prolonged survival after M-2 chemotherapy and adjuvant gallium nitrate (GN) for osteolysis. A retrospective review compared the outcome of 167 patients treated with the M-2 regimen with a cohort of 13 patients (8%) treated with the M-2 protocol + GN. Median survival (from the time of diagnosis) in patients treated with the M-2 regimen was 48 months, while median survival for patients treated with M-2 + GN was 87+ months, a result that markedly exceeded expectations. The authors believed that the administration of GN led to a positive impact on survival of MM patients.

 

 


Giampaolo Talamo, M.D.