Drug treatments for osteoporosis

Question 1

What are the indications for denosumab?

Answer 1

XGEVA

Prolia
-osteoporosis in postmenopausal women and men at increased risk of fractures
- bone loss associated with hormone ablation in men with prostate cancer at increased risk of #
- bone loss associated with long term systemic glucocorticoid therapy in patients at increased risk of

• prevention of skeletal related issues in patients with bone metastases
• giant cell tumour of bone that can’t be operated on

Question 2

What is the pharmacodynamic of denosumab?

Answer 2

A RANK ligand (RANKL) inhibitor

RANKL promotes bone removal/resorption by binding to RANK receptors on osteoclasts

Question 3

What is the pharmacokinetic of denosumab?

Answer 3

Bioavailability = ? but given SC

Protein binding = not available

Half-life = 25.4 days

Metabolism = not available

Excretion = not available

Question 4

What is the dose of Prolia (a denosumab) and how frequently is it given?

Answer 4

60mg every 6 months

Administered into the thigh, abdomen or upper arm

Supplement with calcium and vitamin D

Question 5

What is the dose of XGEVA (a denosumab) and how frequently is it given?

Answer 5

120mg every 4 weeks (for giant cell tumour give additional dose on days 8 & 15 of the 1st month of Tx only)Supplementation of at least 500mg calcium and vitamin D 400 units daily should be taken unless hypercalcaemia is present

Question 6

What are contraindications for denosumab?

Answer 6

Hypocalcaemia

For XGEVA - unhealed lesions from dental or oral surgery

Question 7

What are the serious complications associated with denosumab use?

Answer 7

Atypical femoral fractures - with long term (2.5 or more years) of denosumab Tx of postmenopausal osteoporosis Osteonecrosis of the jaw - in pts receiving 120mg denosumab for cancerHypocalcaemia - risk increases with degree of renal impairmentOsteonecrosis of the external auditory canal - consider in patients with ear symptoms e.g., chronic ear infections or those with suspected cholesteatomaHypercalcaemia after discontinuation of XGEVA for giant cell tumour of bone Increased rate of new primary malignancies (for XGEVA) compared with Zolendronic acidMultiple vertebral fractures

Question 8

Which patient group should not be given denosumab and why?

Answer 8

Under 18s Due to risk of serious hypercalcaemia

Question 9

What should patients on denosumab be advised to report?

Answer 9

Any new or unusual thigh, hip or groin pain during treatment with denosumab - suspicious for atypical femoral fractureConsider discontinuing denosumab in patients suspected of having an atypical femoral fracture

Question 10

What are the risks factors for developing osteonecrosis of the jaw (ONJ) when on denosumab?

Answer 10

Smoking Old agePoor oral hygieneInvasive dental procedures (i.e., tooth extractions, dental implants, oral surgery)Comorbidity (i.e, dental disease, anaemia, coagulopathy, infection)Advanced cancerPrevious Tx with bisphosphonatesConcomitant Tx (i.e., chemo, anti-angiogenic biologics, corticosteroids, radiotherapy to head and neck)

Question 11

What precautions are recommended to reduce risk of ONJ?

Answer 11

For denosumab 120mg (cancer indication)- dental exam + appropriate preventative dentistry before starting treatment - for all patients- do not start denosumab in patients with a dental or jaw condition requiring surgery, or in patients that have unhealed lesions from dental or oral surgeryDenosumab 60mg (osteoporosis indication)- check for ONJ risk before starting Tx. Do a dental exam and appropriate preventative dentistry for patients with risk factors

Question 12

What monitoring is recommended for patients on denosumab?

Answer 12

Plasma [Ca2+] monitoringFor both denosumab 120mg (cancer) and denosumab 60mg (osteoporosis)- before 1st dose- with 2 weeks after intial dose- is suspected symptoms of hypocalcaemia occurFor denosumab 120mg- consider monitoring more frequently in patients with risk factors for hypocalcaemia (e.g., severe renal impairment, creatinine clearance < 30mL/min)Correct hypocalcaemia and vitamin D deficiency before starting. Monitor plasma-calcium concentration during therapy

Question 13

What symptoms of hypocalcaemia should patients on denosumab be advised to report to the doctor?

Answer 13

Muscle spasms Twitches CrampsNumbness or tingling in the fingers, toes or around the mouth

Question 14

What are the common/very common side effects of denosumab?

Answer 14

The usual (i.e., N+V, diarrhoea) plus:- abdo discomfort - alopecia (i.e., hair loss)- constipation- dyspnoea- hyperhidrosis (i.e., increased sweating)- sciatica - hypophosphotaemia- increased risk of infection- skin reactions

Question 15

What are the uncommon side effects of denosumab?

Answer 15

Atypical femur fractureCellulitis (see prompt med attention)Hypercalcaemia (on discontinuation)

Question 16

What are the rare/very rare side effects of denosumab?

Answer 16

Hypersensitivity Hypersensitivity vasculitisFacial swelling (frequency unknown)

Question 17

What should be done for childbearing women before starting them on denosumab?

Answer 17

Ensure they are on effective contraception during Tx and for at least 5 months after stopping Tx

Question 18

TRUE OR FALSEDenosumab should be avoided in pregnancy but can be taken in breastfeeding

Answer 18

FALSEDenosumab should be avoided in both pregnancy and breastfeeding Risk of toxicity increases with each trimester

Question 19

What should be done if a patient misses a Prolia dose?

Answer 19

Give missed dose within 1 month of scheduled date

Question 20

What should you advice patients to do to help avoid ONJ?

Answer 20

Maintain good oral hygiene Receive routine dental check-ups Immediately report any oral symptoms e.g., dental mobility (i.e., loose tooth), pain, or swelling to a doctor and dentist

Question 21

Sources for denosumab

Answer 21

https://bnf.nice.org.uk/drugs/denosumab/https://go.drugbank.com/drugs/DB06643

Question 22

What are the significant drug interactions for denosumab?

Answer 22

Denosumab + cinacalcet = increased risk of hypocalcaemiaDenosumab + etelcalcetide = increased risk of hypocalcaemia

Question 23

What is the indication for bisphosphonates?

Answer 23

Osteoporosis (both women and men)

Question 24

What is the pharmacodynamic of bisphosphonates?

Answer 24

Bind to hydroxyapatite on bones Slows rate of growth and dissolution and hence bone turnoverWhen taken up by the osteoclasts it causes cell apoptosis

Question 25

What are contraindications for alendronic acid?

Answer 25

Abnormality of the oesophagusHypocalcaemia Other factors that delay emptying e.g., achalasia

Question 26

What are the serious complications associated with bisphosphonate use?

Answer 26

Atypical femoral fracturesOsteonecrosis of the jawHypocalcaemia - risk increases with degree of renal impairmentOsteonecrosis of the external auditory canal - consider in patients with ear symptoms e.g., chronic ear infections or those with suspected cholesteatoma

Question 27

What are the risks factors for developing osteonecrosis of the jaw (ONJ) when on bisphosphonates?

Answer 27

potency of bisphosphonate (highest for zoledronate)route of administrationcumulative doseduration and type of malignant diseaseconcomitant treatment, smokingcomorbid conditionsHx of dental disease

Question 28

What precautions are recommended to reduce risk of ONJ when prescribing bisphosphonates?

Answer 28

All patients with cancer and patients with poor dental status should have a dental check-up (and any necessary remedial work should be performed) before bisphosphonate treatment, or as soon as possible after starting treatmentAdvice patients to maintain good good oral hygiene, receive routine dental check-ups, and report any oral symptomsBefore giving IV prescription give patient card to remind them of the risk of ONJ

Question 29

What oral symptoms should patients on bisphosphonates report to a doctor or dentist?

Answer 29

dental mobilitypain, or swellingnon-healing sores or discharge

Question 30

When should patients inform the doctor/dentist that they are on IV bisphosphonates?

Answer 30

If they need dental treatment or dental surgery

Question 31

What should patients be advised to tell doctors/dentist before they start IV bisphosphonates?

Answer 31

any problems with their mouth or teeth before starting treatmentif the patient wears dentures, they should make sure their dentures fit properly

Question 32

What are the risk of developing osteonecrosis of the external auditory canal include for patients on bisphosphonates?

Answer 32

steroid usechemotherapyinfection ear operationcotton-bud use

Question 33

What are the common/very common side effects of bisphosphonates?

Answer 33

Oesophagitis (discontinue if this happens)AlopeciaDecreased appetiteAsthenia (i.e., abnormal physical weakness or lack of energy)Renal impairment Altered tasteEye inflammationGastritis Arthralgia

Question 34

What are the uncommon side effects of bisphosphonates?

Answer 34

Anaphylactic reactionAngioedema Bronchospasm Oesophageal stenosis (discontinue of this happens)Osteonecrosis

Question 35

What are the rare side effects of bisphosphonates?

Answer 35

Atypical femur fracture Stevens-Johnsons syndrome

Question 36

What should patients on bisphosphonates be advised to report apart from those related to ONJ?

Answer 36

Any new pain in the groin, hip or thighs

Question 37

When should treatment be reviewed for the different bisphosphonates?

Answer 37

After 5 or more years = alendronic acid, risedronate sodium or ibandronic acid After 3 or more years = zoledronic acid

Question 38

Which bisphosphonates are given orally?

Answer 38

Alendronic acid RisedronateIbandronic acid

Question 39

How should patient’s be advised to take oral bisphosphonates?

Answer 39

Manufacture advices to have it with plenty of water, on an empty stomach, sitting upright /standing and at least 30 mins before breakfastPatient should stand or sit upright for at least 30 minutes after administration.FROM VERSUSARTHRITISTake it on an empty stomach with plain tap water. Other drinks may prevent the drug being properly absorbed by the body.Avoid eating or drinking anything other than tap water Avoid taking any other medication or supplements or food for at least 30 minutes afterwards (45 minutes for Bonviva) - this is to help ensure the medication is effectively absorbed.Need to stay upright (sitting, standing or walking) for up to 1 hour afterwards to prevent the medication flowing back from your stomach and causing heartburnAvoid lying down after taking bisphosphonates until after they’ve eaten

Question 40

What is the typical dose of alendronic acid?

Answer 40

WOMEN 10mg PO OD/70mg once weekly MEN10mg PO OD

Question 41

What monitoring should be done for alendronic acid before and during treatment

Answer 41

Before = calcium and minerals e.g., vitamin D. Correct any abnormalities or deficiencies before starting TxDuring = serum [Ca2+]

Question 42

What are contraindications for risedronate sodium?

Answer 42

Hypocalcaemia

Question 43

What are the typical doses of risedronate sodium?

Answer 43

Paget’s disease of the bone = 30mg PO OD for 2 months (may be repeated if necessary for at least 2 months)Tx of postmenopausal osteoporosis to reduce risk of hip fracture = 5mg PO OD / 35mg PO once a weekPrevention of osteoporosis in postmenopausal women = 5mg PO ODTx of osteoporosis in men at high risk of fractures = 35mg PO once a week

Question 44

What is the typical dose of zoledronic acid?N.B. zoledronic acid is only through IV

Answer 44

Prevention of skeletal related events in advanced malignancy involving bone = 4mg every 3–4 weeks, calcium 500 mg daily and vitamin D 400 units daily should also be takenTumour-induced hypercalcaemia (specialist use only) = 4mg for 1 dosePaget’s disease of bone (for specialist use only) = 5mg for 1 dose at least 500 mg elemental calcium twice daily (with vitamin D) for at least 10 days is recommended following infusionOsteoporosis in men and postmenopausal women = 5mg once yearly as a single dose in patients with recent low-trauma hip fracture, dose should be given at least 2 weeks before hip # repair: before first infusion give 50 000–125 000 units of vitamin DFracture prevention in osteopenia [hip or femoral neck] = 5mg once every 18 months as a single dose

Question 45

What monitoring should be done for zoledronic acid?

Answer 45

Correct disturbances of calcium metabolism (e.g. vitamin D deficiency, hypocalcaemia) before starting. Monitor serum electrolytes, calcium, phosphate and magnesium.Monitor renal function in patients at risk, such as those with pre-existing renal impairment, those of advanced age, those taking concomitant nephrotoxic drugs or diuretics, or those who are dehydrated.