Safety nel trattamento con bisfosfonati/denosumab per la prevenzione della CTIBL

(1)

Safety nel trattamento

con bisfosfonati/denosumab per la prevenzione della

Cancer Treatment Induced Bone Loss (CTIBL)

SC Oncologia Medica Ospedale Fatebenefratelli

Dr.ssa Nicla La Verde

(2)

 BISPHOSPHONATES

 DENOSUMAB

ONCOLOGIA MEDICA FATEBENEFRATELLI

(3)

THERAPY WITH BONE ANTIRESORPTIVE AGENTS ADVERSE EVENTS

 Literature Overview

 Severe Adverse Events

 Patients’ forum

 Conclusions

(4)

LITERATURE OVERVIEW

(5)

Bhoopalam et al. J Urology 2009

(6)

Eidtmann et al Annals of Oncology 2010

Adverse events occuring in >5% of patients in the safety population

(7)

Cummings, NEJM 2009

(8)

 Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Denosumab), urinary tract (0.5%

placebo vs. 0.7% D), and ear (0.0% placebo vs. 0.1% D) were reported.

 Endocarditis was reported in no placebo patients and 3 patients receiving D

 Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with D(< 0.1% placebo vs. 0.4% D)

 In the Freedom study, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Denosumab groups

SERIOUS INFECTION

(9)

 Overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Denosumab groups

 New malignancies related to

 breast (0.7% placebo vs. 0.9% D)

 reproductive system (0.2% placebo vs. 0.5% D)

 gastrointestinal system (0.6% placebo vs. 0.9% D)

 A causal relationship to drug exposure has not been established

NEW MALIGNANCIES

(10)

Ellis, JCO 2008

(11)

Gnant, Lancet 2015

(12)

Smith, NEJM 2009

Cataracts 1.2% placebo vs. 4.7% D

(13)

Smith, NEJM 2009

(14)

S C R E E N I N G

Denosumab 60 mg SC Q6M

year 1 D

A Y

1 Alendronate

70 mg oral QW Denosumab 60 mg SC Q6M

Alendronate 70 mg oral QW

year 2

E N D O F T H E S T U D Y Crossover

0-35 days 24 months

Randomization

1:1 6 12 18

Visits 24 months

N = 250

Multicentric, randomized, open label, crossover Kendler DL et al. Osteoporos Int 2011; 22: 1725‐1735 Freemantle N et al. Osteoporos Int 2012;23: 317‐326

(15)

Kendler DL et al. Osteoporos Int 2011; 22: 1725‐1735

0 5 10 15 20 25

No Aderence

No

Compliance No

Continuation RRR = 46%

P= 0.026 RRR = 52%

P= 0.014 RRR = 50%

P= 0.029 Denosumab (N = 126) Alendronate (N = 124)

RRR = Relative Risk Reduction

Year 1

% patients

(16)

SEVERE ADVERSE EVENTS

(17)

1. Hypocalcemia and other electrolyte abnormalities

2. Atypical fractures

3. Osteonecrosis of the jaw

Severe adverse events

(18)

HYPOCALCEMIA

AND OTHER ELECTROLYTE

ABNORMALITIES

(19)

 Hyperparathyroidism

 Thyroid or parathyroid surgery

 Malabsorption syndromes

 History of small bowel resection

 Severe renal impairment

 Dialysis

HYPOCALCEMIA: Anamnesis

(20)

 Calcium: 1000 mg daily (diet plus supplement)

 Vitamin D: 800 to 1200 IU daily

 Vitamin D: dosage of serum basal levels known

 Periodic monitoring of serum calcium levels

HYPOCALCEMIA: Prevention

(21)

 Oral calcium and vitamin D supplementation

 IV calcium supplementation (rarely)

 Serum dosage of magnesium

 Warning: sometimes need of albumin‐adjusted serum calcium!

HYPOCALCEMIA: Treatment

(22)

ATYPICAL FRACTURES

(23)

1. Subtrochanteric and diaphyseal femoral fractures 2. After minimal or no trauma

3. Warning for thigh or groin pain

ATYPICAL FRACTURES

(24)

1. Bilateral in up to 40 to 50 % of cases

2. Circumferential cortical thickening and cortical stress lesions are often seen on radiographs preceding the fracture

ATYPICAL FRACTURES

(25)

OSTEONECROSIS OF THE JAW

(26)

Pts needs the following characteristics

 Current or previous treatment with antiresorptive or antiangiogenic agents

 Exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region that has persisted for more than eight weeks

 No history of radiation therapy to the jaws or obvious metastatic disease to the jaws

MEDICATION RELATED ONJ

(27)

(28)

(29)

(30)

BASAL

2 YEARS LATER

3 YEARS LATER

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Rathbone, JCO 2013

 1681 early breast cancer pts

 26 confirmed cases of ONJ

 2.1% (95% CI, 0.9% to 3.3%)

 74% returned the OHIP‐14 questionnaire.

Neither the prevalence nor severity of impacts on Oral‐QoL differed signiﬁcantly between zoledronate patients and control patients.

(32)

Shapiro, JCO 2012

Among the relevant questions to women with breast cancer receiving zoledronic acid or denosumab are

“What are my chances of developing BONJ, and if I do, how does the disease and its treatment affect my life in the short‐and long‐term?

”The answer to the ﬁrst part of that question is clearly low ‐ between 0.2% to 2%, depending on whether the treatment is intended to prevent/treat osteoporosis, prevent skeletal metastases in the context of a clinical trial, or treat skeletal metastases.

Safety nel trattamento con bisfosfonati/denosumab per la prevenzione della CTIBL