Lecture 17 - Bone Modifying Agents

Question 1

Hypercalcemia of malignancy epidemiology

Answer 1

20-30% of all cancer pts due to increased bisphosphonate use
non-malignant causes: primary hyperparathyroidism, meds, renal failure

Question 2

Pathophysiology of HCM

Answer 2

increased parathyroid hormone related prote (PTHrP),
increased calcitriol, increased resorption, decreased elimination, bone metastases

Question 3

HCM etiology

Answer 3

1. humoral: caused by PTHrP; stimulated osteoclasts in bone marrow and renal Ca++ retention
2. local osteolytic hypercalcemia: caused by cytokines and PTHrP
3. 1,25(OH)2D-secreting lymphomas
4. ectopic hyperparathyroidism
5. renal: increased calcium reabsorption, decreased phosphorous reabsorption

Question 4

S/S: mild

Answer 4

polyuria, polydipsia, constipation, anorexia, fatigue

Question 5

S/S: moderate

Answer 5

dehydration, N/V, lethargy, confusion, muscle weakness, loss of deep tendon reflexes, shortened QT, widened T wave

Question 6

S/S: severe

Answer 6

decreased GFR, nephrocalcinosis, seizures, stupor, coma, heart block, arrhytmias, asystole

Question 7

Corrected calcium

Answer 7

serum calcium + 0.8 (4 - serum albumin)
normal calcium: 8.5-10 mg/dL

Question 8

Degree of hypercalcemia

Answer 8

mild: corrected calcium - < 12 mg/dL
moderate: corrected calcium 12-14 mg/dL
severe: corrected calcium > 14 mg/dL

Question 9

Mild HCM (10-12 mg/dL)

Answer 9

asymptomatic or mild sx: encourage hydration, discontinued meds that increase serum calcium or decrease renal blood flow, repeat calcium level in 4 weeks

Question 10

Moderate HCM (12-14 mg/dL)

Answer 10

hydration: 200-400 mL/hr of 0.9% normal saline
bisphosphonate: zoledronic acid OR pamidronate; can be repeated after 7 days if needed

Question 11

Moderate HCM: hydration

Answer 11

lowers calcium by 1.6-2.4 mg/dL
reduces calcium more quickly than bisphosphonate

Question 12

Moderate HCM: bisphosphonate

Answer 12

zoledronic acid shown to be superior to pamidronate

Question 13

Severe HCM (>14 mg/dL)

Answer 13

HYDRATION: typically 200 mL/hr
same bisphosphonates as moderate
calcitonin: used for severe sx or very high calcium or after bisphosphonate (calcium level reductions are small ~1 mg/dL)
hypersensitivity rxns, arthralgias, flushing, nausea

Question 14

Treatment refractory HCM: phosphates

Answer 14

drives calcium into tissues
mild hypercalcemia with normal to low PO4

Question 15

Treatment refractory HCM: gallium nitrate

Answer 15

inhibits bone resorption
for moderate to severe hypercalcemia resistant to hydration
better efficacy than calcitonin

Question 16

Treatment refractory HCM: denosumab

Answer 16

RANK-L inhibitor
used when refractory to other treatments

Question 17

Chronic HCM management

Answer 17

zoledronic acid
pamidronate
risk for AEs increases with repeated doses

Question 18

Comparison of agents

Answer 18

1. 0.9% normal saline
2. bisphosponates
3. calcitonin
4. loop diuretics

Question 19

0.9% normal saline

Answer 19

MOA: dilutes calcium and improves renal elimination
for mild, severe

Question 20

Loop diuretics

Answer 20

MOA: increases urinary calcium excretion
for moderate, severe

Question 21

Bisphosphonates

Answer 21

MOA: blocks bone resorption
for mild, severe

Question 22

Calcitonin

Answer 22

MOA: blocks bone resorption and increases urinary calcium excretion
for severe

Question 23

Intravenous bisphosphonates

Answer 23

affinity for hydroxyapatite
inhibit osteoclast activity through: induce direct osteoclast apoptosis, inhibit differentiation and maturation
decrease bone resorption, increasing mineralization
concentrate at active bone remodeling sites; decrease skeletal morbidity

Question 24

Bone health in cancer

Answer 24

tumor cells secrete cytokines and growth factor
increased production of receptor activate or nuclear factor kappa B ligand (RANK-L)
increased osteoclasts lead to increased bone resorption

Question 25

Epidemiology of bone metastases

Answer 25

cancers with affinity for bone: breast, prostate, myeloma, lung, kidney
usually metastasizes to axial skeleton; can be lytic or blastic lesions

Question 26

Skeletal related events defined as

Answer 26

pathologic fracture
need for bone radiation
need for bone surgery
spinal cord compression
hypercalcemia

Question 27

Diagnosis of SRE’s

Answer 27

sx: bony pain or tenderness
scans: radionucleotide bone scan > radiograph: uptake of radio-tracer at sites of bone formation; increased blood flow indicative of metastases

Question 28

Risk factors for fractures: women: breast cancer

Answer 28

bone mineral density < -.25; on aromatase inhibitors; age > 65; corticosteroid use > 6 mo; BMI < 20; family history of hip fractures, h/o fracture before age 50, smoking

Question 29

Risk factors for fractures: men with prostate cancer

Answer 29

androgen deprivation therapy
smoking

Question 30

Treatment of bone metastases

Answer 30

goal: palliation of sx
radiation; chemo; IV bone modifying agents; radioisotopes

Question 31

Radiation therapy

Answer 31

overall response rates of 85%; pain relief within 1-2 weeks; if pain relief not acheived by 6 weeks, unlikely to see benefit

Question 32

Radiation therapy: radioisotopes

Answer 32

delivered more specifically to tumor; treatment of bone metastases from thyroid cancer with 131-iodine
radium-223 chloride shown benefits in prostate cancer
strontium and samarium used in metastatic breast and prostate cancers

Question 33

IV bisphosphonates for SRE’s

Answer 33

pamidronate: renal adjustment dosing needed
zoledronic acid: renal adjustment dosing needed
NO adjustments warranted if being used for HCM

Question 34

Other conisderations

Answer 34

bisphosphonates: supplement with calcium and vitamin D
zoledronic: more expensive, but shorter infusion time
pamidronate: cheaper, but longer infusion time

Question 35

Denosumab

Answer 35

fully human monoclonal antibody with high affinity for RANK-L

Question 36

Denosumab considerations

Answer 36

can use in pt who fails bisphosphonates
rapidly reduces bone turnover rate
lack of affinity for hydroxyapatite and more evenly spreads throughout bone
may suppress residual osteoclast fx in pts who poorly responds to bisphosphonates

Question 37

Denosumab - xgeva

Answer 37

bone metastases from solid tumors

Question 38

Denosumab - prolia

Answer 38

osteopenia
for women at high risk of fracture and receiving aromatase inhibitors for breast cancer and in men recieving androgen deprivation therapy for prostate cancer

Question 39

Denosumab considerations

Answer 39

correct hypocalcemia prior to initiation
supplement calcium and vit D daily
NO renal dose adjustments (use in pts with renal dysfunction)
very expensive

Question 40

Adverse effects of therapies

Answer 40

osteonecrosis of jaw: caused by invasive dental procedures, poor oral hygiene, and use of dental appliances; oral infection; IV more of a risk than PO
greatest risk: zoledronic, then denosumab, then pamidronate

Question 41

Osteonecrosis of jaw

Answer 41

MOA: angiogenesis suppression; osteocyte depletion leading to avascular necrosis
treatment: palliative, pain control, chlorhexidine and/or antibiotics, conservative surgeries

Question 42

Renal dysfunction

Answer 42

most: zoledronic acid, then pamidronate, then denosumab
bisphosphonate not recommended for CrCL < 30 mL/min
denosumab: not renally eliminated, no renal dosing adjustments needed

Question 43

Other AEs

Answer 43

hypocalcemia - greater risk in denosumab
bone pain, nausea, diarrhea, fatigue

Question 44

Duration of treatment

Answer 44

typically use every 3 month dosing
stop using at 2 years!