Osteoporosis Pharmacology

what do antiresorptive agents do?

reduce bone resorption/breakdown

what do anabolic agents do?

aid in formation of new bone

examples of antiresorptive agents:

bisphosphonates, RANKL inhibitors, estrogens, mixed estrogens agonist/antagonists and tissue selective estrogen complexes, calcitonin, romosozumab

examples of anabolic agents:

PTH analogs, romosozumab

which drugs are bisphosphonates

alendronate (Fosamax, Binosto), risendronate (Actonel, Atelvia), ibandronate (boniva), zoledronic acid (Reclast)

MOA of bisphosphonates

binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, leading to a reduction in bone resorption

PK considerations

poorly absorbed after oral administration

• < 1% bioavailability when administered in fasting state before breakfast

  • decreases by 60% with food or beverage intake

half-life for bisphosphonates

> 10 years

common ADRs of bisphosphonates

nausea/dyspepsia (oral), transient influenza-like illness with injectables (arthralgia/myalgia/HA/fever)

how to help prevent ADRs of bisphosphonate injectables

pre-treat with APAP

rare ADRs of bisphosphonates

GI perforation/ulceration/bleeding (PO), musculoskeletal pain, osteonecrosis of the jaw, atypical fractures

DDI with bisphosphonates

calcium and other multivalent cations decrease absorption, other drugs/foods can also decrease absorption when given simultaneously

dosing for alendronate

5 or 10 mg daily (USE INFREQUENTLY); more commonly used 35-70 mg PO weekly

dosing of risedronate

IR - 5 mg daily, 35 mg weekly, 75 mg given 2 consecutive days/month, or 150 mg monthly

DR - 35 mg PO weekly

dosing for ibandronate

2.5 mg PO daily, 150 mg monthly, or 3 mg IV every 3 months

dosing for zoledronic acid

5 mg IV (over 15 mins) yearly for treatment every 2 years for prevention

when to avoid PO therapy of bisphosphonates

if patient has esophageal stricture, achalasia, inability to remain upright for 30-60 minutes, or increased risk for aspiration

what CrCl should bisphosphonates not be used in?

less than 30-35 mL/min

T/F: bisphosphonates can be given to patients with history of esophageal cancer

false

which bisphosphonates are approved only in women?

ibandronate

what administration issues are present with bisphosphonates

maximizing absorption and minimizing side effects

clinical considerations for alendronate/risondronate IR:

take on an empty stomach, first thing in the morning, wait at least 30 minutes before eating/drinking, remain upright for 30 minutes

clinical considerations for risedronate DR

take with plain water immediately after breakfast, remain upright for 30-60 minutes

clinical considerations for ibandronate

take on an empty stomach, first thing in the morning, wait at least 60 minutes before eating/drinking, remain upright for 60 minutes

what is osteonecrosis of the jaw (ONJ)

exposed, necrotic bone in the maxillofacial region

risk factors for osteonecrosis of the jaw

Invasive dental procedures, cancer, concomitant chemotherapy,
corticosteroids, poor oral hygiene, ill-fitting dentures, comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease)

when does ONJ occur more frequently

patients with cancer taking high dose, IV BPs (some cases reported in antiresorptive OP therapies such as denosumab)

how to manage/prevent ONJ

recommend completion of major dental work prior to beginning therapy

what are the characteristics of atypical femur fractures

unique radiographic features and location (subtrochanteric femur, diaphyseal femur), occur after little or no trauma, often preceded by pain in groin/thigh area (weeks to months prior), biopsies often reveal severely suppressed bone turnover

incidence rate of atypical femus fractures

exact incidence is unknown, accounts for <1% of all hip and femoral fractures

which patients experience the majority of atypical femur fractures

BP-treated patients but unclear if this is the cause (BP therapy for >3-5 years appears to increase risk)

which therapies besides BPs are also associated with atypical femur fractures

antiresorptive therapies (i.e., denosumab)

if an atypical fracture occurs what should be done

discontinue antiresorptive therapy

which drug is a RANKL inhibitor?

Denosumab

MOA of denosumab

human monoclonal antibody that binds to RANKL, which is essential for the formation function, and survival of osteoclasts; prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, decreasing bone resorption and increasing bone mass

dose of denosumab

60 mg SQ every 6 months, administered by healthcare professional

potential ADRs of denosumab

musculoskeletal pain (bone, joint, or muscle), dermatologic reactions (dermatitis, eczema, rashes), hypocalcemia, serious infections (skin, abdomen, urinary tract, ear), ONJ, atypical femur fractures

clinical considerations for denosumab

may cause hypocalcemia (correct pre-existing hypocalcemia prior to therapy), no drug interaction well-documented, bone loss is rapid following discontinuation (consider alternate agents to maintain BMD)

BBW for denosumab

severe hypocalcemia in patients with advanced kidney disease - patients with advanced CKD eGFR < 30 mL/min

MOA for estrogen/hormone therapy

reduce bone resorption by increasing estrogen levels in post-menopausal women (estrogen inhibits release of RANKL)

T/F: only females should receive estrogen/hormone therapy for osteoporosis

true

T/F: estrogen treatments are preferred for prevention/treatment of osteoporosis

false

what are the concerns of using estrogen/hormone therapy long-term?

increased risk of MI, stroke, breast cancer, pulmonary embolism, DVT

MOA of raloxifene

appears to act as an estrogen agonist in bone; it decreases resorption of bone and bone turnover, increases bone mineral density (BMD), and decreases fracture incidence

indications for raloxifene

post-menopausal osteoporosis (females only), reduction in risk of invasive breast cancer in post-menopausal women with osteoporosis

dosage of raloxifene

60 mg PO QD

common ADRs of raloxifene

hot flashes, leg cramps, peripheral edema, gallbladder disease, cataracts (rare)

which drug is an estrogen agonist/antagonist (EAA)?

raloxifene

DDI with raloxifene

none of significance, use with systemic estrogens not recommended

BBW for raloxifene

increased risk of VTE and death from stroke

which drug is a tissue-specific estrogen complex (TSEC) with bazedoxifene/conjugated equine estrogen

Duavee

MOA of Duavee

bazedoxifene is an EAA combined with conjugated equine estrogens, making it a tissue specific estrogen complex; bazedoxifene reduces risk of endometrial hyperplasia —→ concomitant progestin not needed

indication for Duavee

women who suffer from moderate-to-severe vasomotor symptoms associated with menopause and to prevent osteoporosis after menopause

dose of Duavee

CEE 0.45 mg + bazedoxifene 20 mg (1 tablet) PO QD

common ADRs of Duavee

muscle spasms, N/D, dyspepsia, upper abdominal pain, oropharyngeal pain, dizziness, neck pain

BBW for Duavee

endometrial cancer, cardiovascular disease, and dementia

how should estrogens be prescribed?

prescribe at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman

MOA of salmon calcitonin

the actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated, although calcitonin receptors have been discovered on osteoclasts and osteoblasts; single injections of calcitonin cause a marked transient inhibition of the ongoing bone resorption process; with prolonged use, there is a persistent, smaller decrease in rate of bone resorption

dose of salmon calcitonin

nasal spray: 1 spray (200 units) in one nostril once daily, alternating nostrils

SQ injections are available

indication for salmon calcitonin

treatment of osteoporosis in women who are at least 5 years post-menopausal when alternative treatments are not suitable

common ADRs of salmon calcitonin

rhinitis, epistaxis, symptoms of nose, headache, arthralgia, back pain

DDI for salmon calcitonin

none

what is a risk of salmon calcitonin?

allergic reactions possible in patients with salmon allergy

MOA of PTH analogs

administration stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity

how long can patients receive PTH analogs for?

should not exceed 24 months of treatment

T/F: once treatment with PTH analogs is stopped, bone loss can be rapid, and an alternative agent should be started

true

warnings/precautions of PTH analogs

osteosarcoma

who would be at increased baseline risk for osteosarcoma?

those with metabolic bone disease (e.g., Paget’s Disease), bone metastases, history of skeletal malignancies, previous radiation to the skeleton

which drugs are PTH analogs

teriparatide (Forteo) and abaloparatide (Tymlos)

how are PTH analogs administered?

SQ once daily

common ADRs of teriparatide

leg cramps, dizziness/orthostatic hypotension, pain/arthralgia, nausea, cough, injection site reaction, hypercalcemia

common ADRs of abaloparatide

dizziness/orthostatic hypotension, palpitations, nausea, hyperuricemia, hypercalciuria, injection site reactions, hypercalcemia

which PTH analog is only approved for females?

abaloparatide

which drug is a scletostin inhibitor?

romosozumab (Evenity)

MOA of romosozumab

humanized monoclonal antibody that binds to sclerostin; increases osteoblast synthesis, differentiation, and bone matrix building; decreases RANKL and increases OPG

which drug increases bone formation and decreases bone resorption?

romosozumab

how long can patients be on romosozumab

limit therapy to 12 months

why should romosozumab be limited to 12 months of use?

anabolic effect wanes after 12 months and has a BBW for MI, stroke, and cardiovascular death

dosing of romosozumab

210 mcg SQ once monthly given as 2 separate 105 mcg injections

ADRs of romosozumab

nasopharyngitis, arthralgia, injection site reactions, hypocalcemia, ONJ, atypical femur fracture.

which drugs do not have data for preventing hip fractures?

bazedoxefine ± CEE, calcitonin, raloxifene, and PTH analogs

which drugs decrease risk of vertebral fracture, nonvertebral fracture, and hip fracture

bisphosphonates and denosumab