Bone Modifying Agents and Hypercalcemia

Question 1

Epidemiology

20 – 30% of all cancer patients
– decreased due to increased ___ use
Most common tumor types
– Lung – 35%
– Breast – 25%
– Hematologic – 14%
– Genitourinary – 6%

Answer 1

bisphosphonate

Question 2

Pathophysiology of HCM

• ___ parathyroid hormone related protein (PTHrP)
• ___ calcitriol
• ___ resorption
• ___ elimination
• Bone metastases

Answer 2

increased
increased
increased
decreased

Question 3

HCM Etiology

1. Humoral (80% of cases)
2. Local osteolytic hypercalcemia
   (20% of cases) Caused by cytokines and PTHrP
3. 1, 25(OH)2D-Secreting Lymphomas
4. . Ectopic hyperparathyroidism
5. 5. Renal (increased ___ reabsorption, Decreased ___ reabsorption)

Answer 3

• calcium
• phosphorus

Question 4

Corrected Calcium

Serum Calcium + 0.8 (4 – Serum Albumin)

Answer 4

Normal Calcium: 8.5-10 mg/dL

Question 5

Mild HCM (10-12 mg/dL)

Asymptomatic or mild symptoms
- Encourage hydration
- Discontinue medications that increase serum calcium or decrease renal blood flow
- Repeat calcium level in 4 weeks

Moderate symptoms
– Hydration: 200 - 400 mL/Hr of 0.9% normal saline
– Bisphosphonate: ___ or ___
* Can be repeated after 7 days if needed

Answer 5

Zoledronic acid or Pamidronate

Question 6

Moderate HCM (12 – 14 mg/dL)

T or F: hydration reduces calcium more quickly than a bisphosphonate and Loop diuretics should be reserved for patients who develop fluid overload

Answer 6

T

Question 7

Moderate HCM (12 – 14 mg/dL)

Bisphosphonate
- ___ Acid
- superior to pamidronate for treatment of moderate to severe hypercalcemia

Answer 7

Zoledronic

Question 8

Severe HCM (> 14 mg/dL)

Hydration, Hydration, Hydration!!
– Typically, ___ mL/Hr

Bisphosphonates

Calcitonin
- ___ after 48 hours
- Hypersensitivity reactions, arthralgias, flushing, or nausea

Answer 8

200
Tachyphylaxis

Question 9

FDA approved
refractory HCM

Answer 9

Denosumab

Question 10

Chronic HCM Management

___ and ___

Answer 10

zoledronic acid, pamidronate

Question 11

Comparison of Agents

Answer 11

NS and bisphosphonates = mild + severe
loop diuretics = moderate + severe
calcitonin = severe

Question 12

Intravenous Bisphosphonates

Affinity for ___
Inhibit osteoclast activity through:
- Induce direct osteoclast apoptosis
- Inhibit differentiation and maturation

• Decreasing bone ___
• Increasing mineralization
• Concentrate at active bone remodeling sites

Answer 12

hydroxyapatite
resorption

Question 13

Bone in Cancer Patients

Tumor cells secrete cytokines and growth factor
* increased production of receptor activate or nuclear factor kappa B
ligand ( ___ )
* increased osteoclasts lead to more bone ___

Answer 13

RANK-L
resorption

Question 14

Epidemiology of Bone Metastases

Cancers with affinity for bone
* ___
* ___
* Myeloma
* ___
* Kidney

• Usually metastasizes to the ___ skeleton

Answer 14

• breast
• prostate
• lung
• axial

Question 15

Skeletal Related Events (SRE’s)

Defined as:
1. Pathologic fracture
2. Need for bone radiation
3. Need for bone surgery
4. Spinal cord ___
5. Hyper ___

s/s
- Bony pain or tenderness

Radionucleotide bone scan > radiograph

Answer 15

compression
hypercalcemia

Question 16

Risk Factors for Fractures

Women: Breast Cancer
* Bone mineral density < -2.5
* On aromatase inhibitors
* Age > 65
- ___ use > 6 months
* BMI < 20 kg/m 2
* Family history of hip fractures
* History of fracture before age of 50
* Smoking

Men with Prostate
Cancer
* Androgen deprivation
therapy
* Smoking

Question 17

Treatment of Bone Metastases

Goal: Palliation of
symptoms
* Radiation
* Chemotherapy
* IV bone modifying
agents
– Delays time to first
SRE by 50%
* Radioisotopes

Question 18

Radiation Therapy
* Overall response rates of 85%
* Pain relief within 1 to 2 weeks
– If pain relief not achieved by 6 weeks, unlikely
to see benefit
– No difference between single and multiple
fractions
– Limited by life-time limits of radiation within
certain areas

Question 19

Radioisotopes
- Delivered more specifically to the tumor
- Treatment of bone metastases from thyroid cancer with 131-Iodine
- Radium-223 chloride shown overall survival benefits in ___ cancer
- Strontium and samarium used in metastatic breast and prostate cancers
- Expensive and have toxicities ( ___ )

Answer 19

prostate
myelosuppression

Question 20

T or F: no renal adjustments are warranted if these agents (zoledronic acid and pamidronate) are for HCM

Answer 20

T

Question 20

V Bisphosphonates for SRE’s

___ :90 mg IV over 2 hours every 3 to 4 weeks
– Renal adjustment dosing needed

___ acid : 4 mg IV over 15 minutes every 3 to 4 weeks or every 12 weeks
– Renal adjustment dosing needed

Answer 20

pamidronate
zoledronic

Question 21

Bisphosphonates
– Supplement with ___ and ___

Answer 21

calcium
vitamin D

Question 22

Denosumab

Fully human monoclonal antibody with high affinity for ___
- Rapidly reduces bone turnover
- Lack of affinity for hydroxyapatite and more evenly spreads throughout bone
- May suppress residual ___ function in patients who poorly responds to bisphosphonates

Bone metastases from solid tumors - ___

For women at high risk of fracture and
receiving aromatase inhibitors for breast cancer and in men receiving androgen deprivation therapy for prostate cancer – ___

Answer 22

• RANK-L
• osteoclast
• Xgeva
• Prolia

Question 23

Denosumab Considerations

• Correct ___ prior to initiation
• Supplement calcium and Vitamin D daily
• NO renal dose adjustments

Answer 23

hypocalcemia

Question 24

Adverse Effects of Therapies

Osteonecrosis of ___
- Angiogenesis suppression
- Osteocyte depletion leading to avascular necrosis

Possible treatment options:
– Palliative, pain control, chlorhexidine and/or antibiotics, conservative surgeries

Agent discontinuation may be associated with slow improvement but may not return to normal

Answer 24

jaw

Question 25

Renal Dysfunction in this Setting

Zoledronic acid > pamidronate > denosumab

Bisphosphonate
- Not recommended for CrCl < ___ mL/min

Denosumab
- Not renally eliminated
- No renal or hepatic dosing adjustments
- No specific dosing recommendations for those on dialysis

Answer 25

30

Question 26

Other Adverse Effects

Hypocalcemia:
- ___&raquo_space; zoledronic acid
- Patients should be supplemented with daily calcium and vitamin D when using for prevention of SRE’s
* Bone pain
* Nausea
* Diarrhea
* Fatigue

Answer 26

Denosumab

Question 27

Duration of Treatment

In clinical practice, typically will use every ___
month dosing

Answer 27

3