Therapeutics III > Lecture 11a: Bone Modifying Agents > Flashcards

Lecture 11a: Bone Modifying Agents Flashcards

(53 cards)

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1
Q

Hypercalcemia of Malignancy (HCM) epidemiology

A

-20-30% of all cancer pt
-dec due to inc bisposphonate use
-most common tumor types: Lung (35%), breast (25%), hematologic (14%), Genitourinary (6%)
-causes: primary hyperthyroidism, meds, renal failure

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2
Q

Normal Bone homeostasis

A

-absorption = elimination
-calcium fluxes
-intestine, bone, soft tissue, extracellular, out through the kidney

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3
Q

Patho of HCM

A

-inc parathyroid hormone related protein (PTHrP)
-inc calcitriol
-inc resorption
-dec elimination
-bone metastases

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4
Q

HCM etiology

A
  1. humoral (80%)
  2. Local osteolytic hypercalcemia (20%)
  3. 1,25(OH)2D-secreting lymphomas (rare)
  4. Ectopic hyperparathyoridism
  5. Renal
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5
Q

Humoral HCM

A

-80% of cases
-caused by PTHrP
-stimulated osteoclasts in bone marrow and renal Ca++ retention
-head/neck, lung, cerical, esophageal, ovarian, endometrial, renal, breast

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6
Q

Local Osteolytic Hypercalcemia HCM

A

-20%
-caused by cytokines and PTHrP

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7
Q

Renal HCM

A

-inc Ca reabsorption
-dec phosph reabsorption

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8
Q

Mild HCM sx

A

-polyuria/dipsia
-constipation
-anorexia
-fatigue

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9
Q

Moderate HCM sx

A

-dehydration
-N/V
-lethargy
-confusion
-weakness
-loss of tendon reflex
-short QTc interval
-widened T wave

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10
Q

Severe HCM sx

A

-dec GFR
-nephrocalcinosis
-seizures
-stupor
-coma
-heart block
-arrhythmias
-asystole

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11
Q

Corrected Calcium!

A

serum Ca + 0.8 (4 - serum albumin)

-normal: 8.5-10mg/dL

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12
Q

Degree of hypercalcemia by correct calcium levels

A

-mild: <12mg/dL
-mod: 12-14 mg/dL
-severe: >14mg/dL

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13
Q

pt specific considerations for hypercalcemia

A

-age
-renal dysfunction
-location of metastases

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14
Q

Mild HCM (asx or mild sx) tx

A

-10-12mg/dL
-hydrate
-d/c meds that inc Ca or dec renal flow
-repeat level in 3-4 weeks

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15
Q

Mild HCM w moderate sx tx

A

-hydration
-200-400mL/h of 0.09% normal saline
-bisphosphonate
=zoldrenic acid 4mg IV over 15 min OR pamidronate 30-90mg IV over 2h
-can repeat after 7 days if needed

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16
Q

Bisphosphonates + Dosing

A

-zoledronic acid 4mg IV over 15 min

OR

-Pamidronate 30-90mg IV over 2h (mild HCM w mod sx only)

-may repeat after 7 days

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17
Q

Moderate HCM tx

A

-12-14mg/dL
-hydration lowers Ca by 1.6-2.4 in 12-24h (better than bisphosphonate)
-loops should be reserved for pt that develop fluid overload
-zoledronic acid 4mg IV over 15 min better than pamidronate (can repeat in 7 days)

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18
Q

Severe HCM tx

A

->14mg/dL
-HYDRATE (usually 200mL/h)
-zoledronic acid 4mg over 15 min (repeat in 7 days)
-calcitonin (4IU/kg IM or SQ q12h)
-calcitonin can be admin before zoledronic acid by Ca level reductions are small (~1mg/dL)

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19
Q

Calcitonin

A

-tx severe HCM
-4IU/kg IM or SQ
-q12h
-max: 8IUkg q6h
-tachyphalaxis after 48 hours
-used for severe sx or very high calcium or after bisphosphonate
-calcitonin can be admin before zoledronic acid by Ca level reductions are small (~1mg/dL)

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20
Q

Severe HCM notes

A

-hypersensitivity reactions
-arthralgias
-flushing
-nausea
-calcitonin can be admin before zoledronic acid by Ca level reductions are small (~1mg/dL)

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21
Q

Options for treatment refractory HCM

A

-phosphates
-gallium nitrate
-denosumab

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22
Q

Phosphates for tx-refract HCM

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A

1-3g daily divided
-drives calcium to tissues
-mild hypercalcemia w normal/low phosphorus
-caution in mod-severe HCM
-may induce metastatic calcification
-Nausea/diarrhea

23
Q

Gallium Nitrate

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A

-200mg for 5 days CIVI
-inhibits bone resorption
-tx mod-severe HCM resistant to hydration
-better than calcitonin
-no comparisons to zoledronic acid

24
Q

Denozumab

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A

-120mg SQ monthly
-RANK-L inhibitor
-refract to other tx
-FDA approved refract HCM

25
Chronic HCM managment
-zoledronic acid 4mg over 15 min IV MONTHLY -pamidronate 90mg IV over 2h MONTHLY -risk of ADR inc w more doses
26
Comparison of HCM agents
-normal saline -bisphosphonates -calcitonin -loops
27
IV bisphosphonates
-affinity for hydroxyapatite -inhibit osteoclast activity through inc osteoclast apoptosis and inhibiting differentiation/maturation -dec bone resorption -inc mineralization -concentrates at active bone remodeling sites -dec skeletal morbidity by 1/3
28
Slide 20 example
=calculations please practice
29
Normal bone
-constant state of remodeling -osteoclasts balance w osteoblasts
30
Bone in cancer patients
-tumor cells secrete cytokines and growth factor -inc production of RANK-L -inc osteoclast = inc bone resorption
31
Formation of bone metastases
32
Cancers w affinity for bone
-prostate -myeloma -breast -lung -kidney -usually metastasizes to axial skeleton -can be lytic or blastic lesions
33
Skeletal Related Events (SRE's) definition
1. pathological fracture 2. need for bone radiation 3. need for bone surgery 4. Spinal cord compression 5. Hypercalcemia
34
Diagnosis of SRE's
-bony pain or tenderness -radionucleotide bone scan better than radiograph -CT can show bony destruction and soft tissue involvement -MRI helpful in pt w normal X-rays and positive bone scans -PET scan
35
Radionucleotide bone scan
-scan for SRE -better than radiograph -uptake of radio-tracer at sites of bone formation -inc blood flow indicative of metastases
36
Risk factors for fractures in women w breast cancer
37
Risk factors for fractures in men w prostate cancer
-androgen deprivation tx -smoking
38
Treatment of Bone metastases
-goal: palliation of sx -radiation -chemo -IV bone modifiying agents (delays time to first SRE by 50%) -radioisotopes
39
Radiation Therapy
-overall response rates of 85% -pain relief within 1-2 weeks -if no pain relief in 6 weeks, usually no benefit -no dif between single and multiple fractions of tx -limited by life-time limits of radiation within areas (can't reirradiate areas over and over) -radioisotopes
40
Radioisotopes
-radiation therapy -delivered more specifically to the tumor -tx of bone metastases from thyroid cancer w 131-Iodine -Radium-223 chloride shown overall survival benefits in prostate cancer -strontium and samarium used in metastatic breast and prostate canncers (expensive and bad myelosuppression)
41
IV bisphosphonates for SREs
-pamidronate 90mg IV over 2h q3-4 weeks -Zoldronic acid 4mg IV over 15min q3-4 weeks OR EVERY 12 weeks -renal adj dosing needed
42
Renal dosing adjustments
43
44
Bisphosphonate considerations in SRE tx
-supplement w Ca and vitamin D due to hypocalcemia -zoledronic shorter infusion but $70 -pamidronate longer infusion but cheaper
45
Denosumab
-fully human mAb w RANK-L affinity -rapidly reduces bone turnover -lack of affinity for hydroxyapatite and more evenly spreads through bone -may suppress residual osteoclast function in pt who poorly respond to bisphosphonates
46
Denosumab use/dose
-Xgeva 120mg SQ q4weeks for bone metastases from solid tumors -Prolia 60mg SQ q6months -for women at high risk of fracture and receiving aromatase inhibitors for breast cancer and in men receiving androgen deprivation tx for prostate cancer
47
Densumab consideration
-correct hypocalcemia prior to initiation -supplement daily Ca and Vit D -NO renal adj -$2500/dose
48
Osteonecrosis of jaw cause
-cause by invasic dental procedures, poor hygiene, dental appliance use =oral infection -worse in monthly vs yearly dosing -worse IV than PO dose -Zoledronic/Denosumab worse than pamidronate -refer for baseline dental evaluation and interventions prior to start of tx if possible
49
Osteonecrosis of jaw MOA
-angiogenesis suppression -osteocyte depletion = avascular necrosis
50
Osteonecrosis of Jaw tx
-palliative -pain control -chlorhexidine +/- antibiotics -conservative surgeries -agent d/c may = slow improvement but not likely to return to normal
51
Renal dysfunction in ?
1. Zoldedronic acid 2. Pamidronate 3. Denosumab this might be wrong order -bisphos not recommended for CrCl< 30mL/min -denosumab not renally eliminated, no dose adj
52
Other side effects
-Hypocalcemia (denosumab >> zoledronic acid) -pt should be supplemented w Ca and Cit D daily if using for SRE prevention -bone pain -Nause/diarrhea -fatigue -fever/aches for 24 h after
53
Duration of tx
-no trials -extended dosing intervals evaluated in breast/prostate cancer -q4week v q12 week did not change SRE -typically use q3month dosing since no dif in efficacy and less trips to infusion center
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