Lecture 17 - Bone Modifying Agents Flashcards
Hypercalcemia of malignancy epidemiology
non-malignant causes: primary hyperparathyroidism, meds, renal failure
Pathophysiology of HCM
increased parathyroid hormone related prote (PTHrP),
increased calcitriol, increased resorption, decreased elimination, bone metastases
HCM etiology
- humoral: caused by PTHrP; stimulated osteoclasts in bone marrow and renal Ca++ retention
- local osteolytic hypercalcemia: caused by cytokines and PTHrP
- 1,25(OH)2D-secreting lymphomas
- ectopic hyperparathyroidism
- renal: increased calcium reabsorption, decreased phosphorous reabsorption
S/S: mild
polyuria, polydipsia, constipation, anorexia, fatigue
S/S: moderate
dehydration, N/V, lethargy, confusion, muscle weakness, loss of deep tendon reflexes, shortened QT, widened T wave
S/S: severe
decreased GFR, nephrocalcinosis, seizures, stupor, coma, heart block, arrhytmias, asystole
Corrected calcium
serum calcium + 0.8 (4 - serum albumin)
normal calcium: 8.5-10 mg/dL
Degree of hypercalcemia
mild: corrected calcium - < 12 mg/dL
moderate: corrected calcium 12-14 mg/dL
severe: corrected calcium > 14 mg/dL
Mild HCM (10-12 mg/dL)
asymptomatic or mild sx: encourage hydration, discontinued meds that increase serum calcium or decrease renal blood flow, repeat calcium level in 4 weeks
Mild HCM with moderate symptoms
hydration: 200-400 mL/hr of 0.9% normal saline
bisphosphonate: zoledronic acid OR pamidronate; can be repeated after 7 days if needed
Moderate HCM: hydration
lowers calcium by 1.6-2.4 mg/dL
reduces calcium more quickly than bisphosphonate
Moderate HCM: bisphosphonate
zoledronic acid shown to be superior to pamidronate
Severe HCM (>14 mg/dL)
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
Treatment refractory HCM: phosphates
drives calcium into tissues
mild hypercalcemia with normal to low PO4
Treatment refractory HCM: gallium nitrate
inhibits bone resorption
for moderate to severe hypercalcemia resistant to hydration
better efficacy than calcitonin
Treatment refractory HCM: denosumab
RANK-L inhibitor
used when refractory to other treatments
Chronic HCM management
zoledronic acid
pamidronate
risk for AEs increases with repeated doses
Comparison of agents
- 0.9% normal saline
- bisphosponates
- calcitonin
- loop diuretics
0.9% normal saline
MOA: dilutes calcium and improves renal elimination
for mild, severe
Loop diuretics
MOA: increases urinary calcium excretion
for moderate, severe
Bisphosphonates
MOA: blocks bone resorption
for mild, severe
Calcitonin
MOA: blocks bone resorption and increases urinary calcium excretion
for severe
Intravenous bisphosphonates
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
Bone health in cancer
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
Epidemiology of bone metastases
cancers with affinity for bone: breast, prostate, myeloma, lung, kidney
usually metastasizes to axial skeleton; can be lytic or blastic lesions
Skeletal related events defined as
pathologic fracture
need for bone radiation
need for bone surgery
spinal cord compression
hypercalcemia
Diagnosis of SRE’s
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
Risk factors for fractures: women: breast cancer
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
Risk factors for fractures: men with prostate cancer
androgen deprivation therapy
smoking
Treatment of bone metastases
goal: palliation of sx
radiation; chemo; IV bone modifying agents; radioisotopes
Radiation therapy
overall response rates of 85%; pain relief within 1-2 weeks; if pain relief not acheived by 6 weeks, unlikely to see benefit
Radiation therapy: radioisotopes
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
IV bisphosphonates for SRE’s
pamidronate: renal adjustment dosing needed
zoledronic acid: renal adjustment dosing needed
NO adjustments warranted if being used for HCM
Other conisderations
bisphosphonates: supplement with calcium and vitamin D
zoledronic: more expensive, but shorter infusion time
pamidronate: cheaper, but longer infusion time
Denosumab
fully human monoclonal antibody with high affinity for RANK-L
Denosumab considerations
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
Denosumab - xgeva
bone metastases from solid tumors
Denosumab - prolia
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
Denosumab considerations
correct hypocalcemia prior to initiation
supplement calcium and vit D daily
NO renal dose adjustments (use in pts with renal dysfunction)
very expensive
Adverse effects of therapies
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
Osteonecrosis of jaw
MOA: angiogenesis suppression; osteocyte depletion leading to avascular necrosis
treatment: palliative, pain control, chlorhexidine and/or antibiotics, conservative surgeries
Renal dysfunction
most: zoledronic acid, then pamidronate, then denosumab
bisphosphonate not recommended for CrCL < 30 mL/min
denosumab: not renally eliminated, no renal dosing adjustments needed
Other AEs
hypocalcemia - greater risk in denosumab
bone pain, nausea, diarrhea, fatigue
Duration of treatment
typically use every 3 month dosing
stop using at 2 years!
