ic14 drugs for osteoporosis

Question 1

what is the role of RANK ligand in bone resorption and bone growth and relate this to the place RANKL antagonists has in tx of osteoporosis

Answer 1

RANK ligand is released by osteocytes and stimulates osteoclasts to break down bone

RANKL antagonists can prevent this stimulation

Question 2

what is the role of PTH in bone resorption and bone growth and relate this to the place PTH analogues has in tx of osteoporosis

Answer 2

PTH influences balance between osteoclasts and osteoblasts

analogues of PTH can be used to promote bone growth and decr bone breakdown

Question 3

what is the role of sclerostin in bone resorption and bone growth and relate this to the place scleoristin inhibitors has in tx of osteoporosis

Answer 3

sclerostin released by osteocytes acts on sclerostin receptors on osteoblasts and also inhibits Wnt signalling which affects the functioning of osteoblasts and thus affect bone growth which eventually leads to repressing the differentiation of osteoblasts and their ability to grow new bones

thus anti-sclerostin is used to counteract this inhibition so that osteoblasts can grow more bones (anabolic effect)

Question 4

what is the role of vitD in bone metabolism

Answer 4

in a balanced system where Ca absorption meets metabolic demands, normal bone mineralisation is maintained

since vitD is required for Ca absorption, when there is low levels of vitD, Ca reservoir of bone is depleted to correct for low Ca absorption in gut

i) in vitD deficient state, Ca absorption decr and this fall in Ca leads to incr in PTH secretion
ii) since PTH regulates bone resorption and bone growth, PTH incr bone breakdown in order to recover the low Ca in blood
iii) PTH also has effects on renal tubules bc another path for Ca recovery is through reabsorption of Ca after filtration in renal tubule
iv) vitD would typically also interact with PTH to decr tendency of bone breakdown and decr effect of bone growth impairment

Question 5

what are the factors to consider when determining whether to tx for osteoporosis (and so when do we tx and when do we defer)

Answer 5

consider:
i) fracture risk
ii) past fracture
iii) BMD
iv) age
v) risks for falls or bone loss

tend to treat if
i) high
ii) present
iii) low (T<-2.5)
iv) >65yo
v) high

tend to defer if
i) low
ii) absent
iv) higher
v) younger
vi) low

Question 6

what is a tool that can be used to measure fracture risk

Answer 6

FRAX calc tool (calculates major osteoporotic and hip fracture risks)

Question 7

how can osteoporosis be managed (non pharmacotx and pharmacotx)

Answer 7

non pharmacotx:
i) lifestyle (exercise, smoking cessation, decr alcohol intake)
ii) diet (Ca, vitD)

pharmacotx (anti-resorptive agents):
i) bisphosphonates (alendronate PO, risedronate PO, zoledronic acid IV) *firstline
ii) RANKL inhibitor (denosumab SQ)
iii) estrogen (raloxifene)
iv) calcitonin

pharmacotx (anabolic agents):
i) PTH analogue (teriparatide SQ)
ii) sclerostin inhibitor (romosuzumab SQ)

Question 8

what is to note regarding the agents that can be used for management of osteoporosis

Answer 8

note that anti-resorptive agents and anabolic agents are not combined together to use as adjuncts

(but ok to use with agents that replete Ca and vitD)

Question 9

list an eg. for tx of osteoporosis under estrogen drug class and what is the indication, moa, s/e and caution

Answer 9

raloxifene is a selective estrogen receptor modulator (SERM)

indication:
i) bone health in younger women
ii) women whose other menopausal sx also req tx

moa: raloxifene has mixed estrogen receptor agonism and antagonism and will mimic effects of estrogen on bone density

s/e: can reduce risk of some types of breast cancer but still incr risk of blood clots and can cause hot flashes

caution: raloxifene can help maintain bone density but there is incr risk of breast cancer and blood clots which can cause strokes

Question 10

what is the drug class that is first line for tx of osteoporosis and why

Answer 10

bisphosphonates are first line for tx of osteoporosis bc:

i) convenient route of administration
ii) cheap bc generics are avail
iii) adequate efficacy for most pts
iv) no significantly more severe s/e than other options

Question 11

list the eg. of bisphosphonates and what is the moa, s/e, c/i, administration instruction, caution and considerations

Answer 11

alendronate (PO), risedronate (PO), zolendronic acid (IV) are bisphosphonates

moa: slow bone loss by incr osteoclast cell death

s/e:
i) significant (ONJ, AFF, severe bone or joint muscle pain, upper GI mucosa irritation, ocular effects, hypoCa)
ii) for PO (N, abdominal pain, heartburn)
iv) for IV (flu like sx incl fever, malaise, HA, MSK aches)

c/i:
i) hypoCa
ii) esophageal abnormalities
iii) severe renal impairment (<35)
iv) pregnancy
v) breastfeeding
vi) reflux esophagitis

administration:
i) take on empty stomach with at least 240ml of plain water
ii) maintain upright for at least 30mins
iii) space 2hr apart from polyvalent cations
iv) PO given q1w
v) IV given q12m over 15-30min infusion

caution:
i) active upper GI disease
ii) risk factors for developing ONJ

considerations:
i) ensure vitD is repleted before initiating if deficient
ii) generics avail ($ for PO, $$ for IV)

Question 12

list an eg. of RANKL inhibitor, and what is the moa, s/e, c/i, administration, caution, considerations

Answer 12

denosumab (SQ) is a RANKL inhibitor

moa: human mAb against RANKL to prevent development of osteoclasts

s/e:
i) MSK aches
ii) N/V/D/C
iii) slight tiredness
iv) incr cholesterol levels
v) severe s/e incl hypoCa, cellulitis (incr risk of skin infection), angioedema, ONJ, AFF

c/i:
i) hypoCa
ii) pregnancy

administration:
i) given q6m into the fatty tissues of abdomen

caution:
i) in renal impairment (esp <10)
ii) eczema

considerations:
i) ensure vitD is repleted before initiating if deficient
ii) cost considerations ($$)
iv) do not discontinue bc may incr risk of spinal column fracture when discontinued
v) similar or better bone density results to bisphosphonates

Question 13

what can be administered if there if vitD deficiency but wishes to start on tx for osteoporosis

Answer 13

co administer 1000mg Ca with at least 400IU vitD daily

Question 14

list an eg. of a PTH analogue and what is the moa, s/e, c/i, administration and considerations

Answer 14

teriparatide (SQ) is a PTH analogue

moa: stimulates new bone formation and incr bone strength

s/e:
i) serious calciphylaxis and worsening of prev stable cutaneous calcification
ii) transient orthostatic hypotension
iii) transient and minimal elevations of serum Ca (or hyperCa)
iv) osteosarcoma (in mice)

c/i:
i) hypersensitivity
ii) pre existing hyperCa
iii) skeletal malignancies or bone metastases (hx of bone radiation)
iv) other metabolic bone diseases (paget’s disease, hyperPTH)
v) unexplained elevations of alkaline phosphotase
vi) prev implant or external bean radiation tx to skeleton
vii) hereditary disorders predisposing to osteosarcoma
viii) severe renal impairment (<30)
ix) pregnancy

administration:
i) QD into fatty tissues of the abdomen (max lifetime duration of 2yrs due to potential risk of osteosarcoma)

considerations:
i) cost consideration ($$$$)

Question 15

list an eg. of a sclerostin inhibitor and what is the moa, s/e, c/i, administration, caution and considerations

Answer 15

romosozumab (SQ) is a sclerostin inhibitor

moa: humanised mouse mAb against sclerostin and removes the sclerostin inhibition on Wnt signalling pathway that regulates bone growth thus leading to incr bone formation and decr bone resorption

s/e:
SEVERE
i) MI
ii) incr risk of CV death, stroke
iii) transient hypoCa
iv) hypersensitivity
v) ONJ
vi) AFF

c/i:
i) hypersensitivity
ii) uncorrected hypoCa
iii) hx of MI or stroke (within preceding yr)

administration:
i) q1m for 12m into fatty tissues of the abdomen

caution:
i) severe renal impairment (<30)
ii) prev CVS or stroke events

considerations:
i) cost consideration ($$$$)

Question 16

what should we check for before initiating tx for osteoporosis

Answer 16

i) SCr to calc CrCl to ensure pt’s renal func not c/i for selected agent
ii) serum 25(OH)vitD: replete through supplementation and diet if low
iii) serum Ca: replete through supplementation and diet if low (note that Ca supplementation is routine even if there is no renal impairment)

Question 17

what is the most impt thing to check when want to initiate denosumab (compare this to teriparatide)

Answer 17

must check serum Ca bc denosumab dramatically impairs osteoclast func aka it decr bone resorption greatly (since RANKL is crucial for bone differentiation, development and osteoclast func) thus denosumab wil decr blood Ca q drastically and need to ensure blood Ca remains adequate if not cannot contribute to make new bone

vs for teriparatide, PTH is an anabolic agent that blocks suppression of bone growth and allows bone to grow thus it would have less effect on the blood balance of Ca (will not directly have impairment of bone breakdown in order to replenish blood Ca)

Question 18

why is the kidney func so impt to Ca

Answer 18

kidneys are involved in elimination of Ca thus kidney is strongly involved in Ca levels

Question 19

what are the pt counselling points

Answer 19

i) what is osteoporosis
ii) pt’s risk
iii) fracture reduction
iv) route and freq of drug
v) cost
vi) s/e