Bone Targeted Therapies – Bisphophonates, Denosumab

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Bisphosphonates

bisphosphonates

Mechanism of Action

  • The non-nitrogenous bisphosphonates replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with ATP in the cellular energy metabolism. This leads to an overall decrease in the breakdown of bone due to osteoclast apoptosis and death.
  • Nitrogenous bisphosphonates bind and block the enzyme farnesyl diphosphate synthase  (FPPS) in the mevalonate pathway). This causes the disruption of the HMG CoA-reductase pathway and prevents the formation of farnesol and geranylgeraniol that are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation.
  • Bisphosphonates also increase osteoblast secretion of two important cytokines
      • An inhibhitor of osteoclast recruitment
      • Transforming growth factor –B a signal for osteoclast apoptosis.
  • Preclinical studies suggest that it inhibhits the multiple steps involved in bone metastasis.

Pharmacokinetics

  • Poorly absorbed orally, bioavailability is <1%.
  • Calcium containing foods, beverages and medications may reduce oral drug absorption.
  • Bisphosphonates are not metabolised , they are slowly eliminated by renal excretion. Serum half life is in the order of days.
  • Bisphosphonates adsorb to hydroxapatite crystals in bone. Approximately 50% of an iv administered dose accumulates in the skeleton , binding to sites of active bone remodelling.
  • Bisposphonates become inactive after they are incorporated into quiescent bone .

Toxicities/Adverse Effects

  • Asymptomatic hypocalcemia is common.
  • Self limited flu-like acute phase reaction.
  • Renal toxicity
      • Arises from R1 carbon side chain attached to parent molecule.
      • Renal toxicity has been closely associated with high total drug dose, short infusion time, and poor baseline renal function.
      • Dose should be reduce in patients with stable baseline creatinine clearance <60ml/min, witheld if creatinine clearance is <35ml/min or its actively declining.
  • Osteonecrosis of jaw:
      • Most feared complication , exact incidence not known varies from <1% to 9%,comon in maxilla.
      • Risk factors: Poor oral hygiene, dental treatment, trauma , dental appliance.
  • Oral administration causes gastrointestinal toxicity and and erosive esophagitis.
  • Musculoskeletal pain, Peripheral edema
  • Asthenia , fatigue.

Uses/Indications

  • Hypercalcemia of malignancy.
  • Bone lesions from multiple myeloma.
  • Bone metastases from any solid tumor.
  • Osteoporosis.
  • Pagets disease.
  • Glucocorticoid induced bone loss.

*oral calcium 500mg and vitamin D 400IU per day is recommended unless in setting of hypercalcemia.

Types of Bisphosphonates

Zoledronic Acid

Bisphosphonates - zoledronic acid

Availability
  • IV use only, 4 mg/5 mL single-use vial of concentrate.to be diluted in 100ml normal saline infused no less than 15min.
Pharmacokinetics
  • Plasma area under curve rises with renal involvement, half life is 146 hours
  • Distribution: drug binds to bone serum protein binding is 28-53% in vitro.
  • Elimination: unchanged in urine , within 24hrs
Additional Mechanisms of Action

Zoledronic acid also has antitumor and antimetastatic properties

  • Inhibition of angiogenesis,
  • Tumor-cell invasion, and adhesion in bone;
  • The induction of apoptosis;
  • Antitumor synergy with cytotoxic chemotherapy
  • Immunomodulatory effects
Warnings/Precautions
  • In patients with hypercalcemia of malignancy, adequate rehydration is required prior to administration.
  •  Monitor serum creatinine before each dose. Patients with renal impairment may experience increased renal toxicity.
  •  Osteonecrosis of the jaw, especially in patients with poor oral hygiene, dental caries or
  • Bone, joint or muscle pain may occur that may be severe or incapacitating.
  •  Fetal harm may occur with zoledronic acid.
  •  Atypical subtrochanteric and diaphyseal femoral fractures have been reported.
Indications/Uses
  • Bone metastases due to solid tumors, 4mg IV Q3-4weekly.
  • Hypercalcemia of malignancy: 4mg IV given as single dose, may repeat after 7 day if serum calcium does not normalise.
  • Multiple myeloma: 4mg IV Q 3-4 weekly
  • Osteoporosis: 5mg IV every 12 months
  • Osteopenia secondary to androgen deprivation therapy in prostate cancer patients: 4mg IV 3-12months.
Dose Adjustment in Renal Failure

If renal insufficiency is chronic and stable start as follows

  • 5mg———-CrCl=50-60ml/min
  • 3mg———-CrCl=40-49ml/min
  • 3mg ————CrCl=30-39ml/min
  • not recommended if CrCl< 35ml/min
Drug Interactions
  • Aminoglycosides: Hypocalcemic effects can be enhanced.
  • NSAID: GIT and nephrotoxicity may be enhanced.
  • Phosphate supplements: hypocalcemic effects of phosphate supplements can be enhanced.

Pamidronate

Availability
  • Available in 30-mg or 90-mg vials for IV administration.
  • Each 30mg and 90-mg vial contains, respectively, 30 mg and 90 mg of sterile, lyophilized Pamidronate disodium and 470 mg and 375 mg of mannitol, USP.
Indications
  • Hypercalcemia of Malignancy:The recommended dose is 60 to 90 mg given as a single dose IV infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity.
  • Paget’s Disease :The recommended dose is 30 mg daily, as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.
  • Osteolytic Bone Metastases of Breast Cancer :The recommended dose is 90 mg administered over a 2-hour infusion given every 3-4 weeks.
  • Osteolytic Lesions of Multiple Myeloma :The recommended dose is 90 mg administered as a 4-hour infusion given Q 4weekly
Adverse Effects/Toxicities
  • Reactivation of Herpes simplex and Herpes zoster, influenza-like symptoms.
  • CNS: confusion and visual hallucinations, sometimes in the presence of electrolyte imbalance.
  • Skin rash, pruritus.
  • Orbital inflammation, Conjunctivitis
  • Renal: focal segmental glomerulosclerosis, nephrotic syndrome, hematuria
  • Electrolyte abnormalities: hyperkalemia, hypernatremia
  • Allergic reactions, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock

Ibandronate

Ibandronate sodium is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption.

Availability
  • Oral:2.5 mg film-coated tablet for daily oral administration or, 150 mg film-coated tablet for once-monthly oral administration.
  • Intravenous: Available as 3mg in 3ml solution
Pharmacokinetics
  • Ibandronate either rapidly binds to bone or is excreted into urine.
  • Metabolism: not metabolised and 50-60% of administered dose is excreted unchanged in urine.
Indications
  • Treatment of osteoporosis in postmenopausal women: 2.5mg tablet daily or 3mg IV q 3monthly.
  • Bone metastasis in solid tumors: Inj ibandronate 6mg is infused over 2hr Q 4 weekly.
Precautions
  • Mineral Metabolism: Hypocalcemia, Hypovitaminosis D, and other disturbances of bone and mineral metabolism must be treated.
  • Renal Impairment: should not be administered to patients with serum creatinine 2.3 mg/dL or CrCl <30 mL /min.
  • ONJ
  • Atypical fractures

Clodronate

  • Non nitogen containing bisphosphonate :The chemical name of sodium clodronate tetrahydrate is disodium bisphosphonate tetrahydrate.
  • In concentrations which induce inhibition of bone resorption, sodium clodronate has no effect on the normal mineralisation process in bone tissue.
Availability
  • Available as 800 mg tablet  each contains 1000 mg sodium clodronate tetrahydrate, equivalent to 800 mg anhydrous sodium clodronate.
Pharmacokinetics

Absorption

  • As with other bisphosphonates, the gastrointestinal absorption of oral sodium clodronate is low, at around 2%.
  • Due to strong affinity of sodium clodronate to calcium and other divalent cations of food, the intestinal absorption is negligible with
  • Administered 2 hours before breakfast.

Distribution and Elimination

  • Clonodronate is not metabolised and excreted unchanged in urine.
Indications
  • Osteoporosis: A daily dose of 1600 mg should preferably be taken in the morning on an empty stomach together with a glass of plain water or more than two hours after eating or drinking.
  • Treatment of hypercalcaemia of malignancy.
  • Treatment of osteolytic bone metastases due to carcinoma of the breast . The recommended starting dose is 1600 mg daily. Not to exceed 3200mg/d
  • Treatment of osteolytic lesions of multiple myeloma: same dose as in breast cancer
Dose Adjustment in Renal Failure
Degree of Renal Failure Creatinine Clearance (mL/min) Dose
Mild 50-80 1600 mg/day
Moderate 30-50 1200 mg/day
Severe 10-30 800 mg/day

 

Adverse Effects
  • Elevated LDH & transaminases.
  • GIT disturbances
  • Haematological Rare: thrombocytopenia, marrow depression
  • Respiratory :Impairment of respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disorder.

Denosumab

Denosumab

  • Denosumab is a fully human monoclonal antibody for the treatment of osteoporosis, treatment induced bone loss, bone metastases, multiple myeloma.

Availability

  • Available as Single-use vial containing 60 mg in a 1 mL solution.

RANK Signalling Pathway and Denosumab

  • The RANK signalling pathway is important for osteolclast regulation as it is involved in multiple steps in osteoclast maturation.
  • RANKL binding to RANK on the surface of osteoclast precursors causes differentiation into mature osteoclasts promoting their activation and survival.
  • The stimulatory actions of RANKL are naturally suppressed by osteoprotogerin a decoy receptor which acts like a sink for RANKL.
  • Denosumab binds to and inhibhits RANKL with high affinity and specificity. It depletes RANKL and inhibhits bone resorption.

Dosage

  • Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.

Precautions

  • Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily.
  • Hypocalcemia: Must be corrected before initiating drug.
  • Contraindication: hypocalcemia.
  • No renal dose adjustment

Indications

  • Treatment of postmenopausal women with osteoporosis at high risk for fracture .
  • Treatment to increase bone mass in men at high risk for fracture receiving ADT for nonmetastatic prostate cancer.
  • Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.
  • Prevention of skeletal related events in patients with bone metastases from solid tumors.
  • Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma

Adverse Reactions

  • Serious infections including skin infections: May occur, including those eading to hospitalization.
  • Dermatologic reactions: Dermatitis, rashes, and eczema have been reported.
  • Asymptomatic hypocalcemia
  • Osteonecrosis of the jaw.
  • Suppression of bone turnover.
  • Postmenopausal osteoporosis: (> 5%)were: back pain, pain in extremity,hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials.
  • Bone loss due to hormone ablation for cancer: (≥ 10%) were: arthralgia and back pain.Pain in extremity and musculoskeletal pain have also been reported in clinical trial

Role of Bone (Osteoclast) Directed Therapies in Oncology

Hypercalcemia of Malignancy

  • Etidronate,pamidronate and Zoledronate are FDA approved.
  • Zoledronic acid is the preferred bisphosphonate, median duration of normocalcemia was > 30d for Zoledronate vs 18d for Pamidronate. Rate of normocalcemia at day 10 was 87% for Zoldronate vs 70% for pamidronate.
  • Fiazzi et al. Zoledronic acid is superior to Pamidronate in the treatment of hypercalcemia of malignancy, pooled analysis of two RCT.

Multiple Myeloma

  • Multiple myeloma is the most common cancer to involve bone, with more than 80% of patients developing bone lesions.
  • The bone lesions are purely osteolytic in nature and do not heal in the vast majority of patients.
  • Up to 20% of patients will present with a fracture at diagnosis, approximately 40% will sustain a pathologic fracture within the first year of diagnosis, and nearly 60% of patients will develop pathologic fractures over the course of their disease.

Recommendations

  • Myeloma patients with osteopenia based on normal plain radiograph or bone mineral density measurements:  Bisphosphonates IV recommended.
  • Smoldering or indolent MM without lytic disease:  Not recommended
  • Solitary plasmacytoma: not recommended.
  • MGUS:    not recommended.
  • Role in pain control secondary to bony involvement:  Recommended for patients with pain as a result of osteolytic disease and as an adjunctive treatment for patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures.

Type of Bone Directed Therapy

  • Pamidronate : 90 mg IV delivered over at least 2h. Zoledronic acid  : 4mg  IV over 15 min every 3 to 4 weeks. In light of data from Zervas et al1 showing a 9.5-fold greater risk for the development of ONJ with zoledronic acid compared with pamidronate, patients may prefer pamidronate to zoledronic acid until more data become available .
  •  Clodronate is an alternative bisphosphonate approved worldwide

Duration

The Update Committee suggests that therapy with bisphosphonates be administered monthly for a period 2 years with responsive or stable disease, but their further use is at the discretion of the treating physician.

Monitoring

  • Renal function test to be monitored before administration, renal dose adjustment in renal impairment.
  • Monitor for unexplained Albuminuria every 3 -6m (albuminuria>500mg/24hr) in patient receiving Pamidronate . , if  present to monitor every 3-4 weeks ,To stop drug until renal problem  resolves

Breast Cancer

Prevention of treatment related fragility fractures

  • 2% is the annual rate of bone loss during the initial years after the onset of menopause, reducing to ~1% during the next decade.
  • 6% per year is the rate of bone loss in patients with breast cancer receiving AIs
  • Even higher rates of bone loss (approximately 7% annually) in premenopausal women who receive Ais +GnRH agonist

Prevention of skeletal events in Breast cancer with bone metastases

  • The majority (approximately 70%) of patients with advanced breast cancer develop bone metastases.
  • Patients with bone metastases have an increased risk of SREs .
  • In a 2-year randomized clinical trial in patients with bone metastasis from breast cancer, SREs occurred in 68% of patients who did not receive bone-targeted therapy.
  • Without intervention, the average patient will experience 3.7 SREs per year

Prostate Cancer

  • Zoledronic Acid and Denosumab have been approved for Castrate Resistant Prostate Cancer with bone metastasis.
  • In CRPC without bone metastasis-
    • Bisphosphonates trials were negative.
    • Denosumab: significantly increased bone metastasis-free survival, time to bone mets free survival & symptomatic metastasis
  • Currently, the use of bone-targeted agents in men with castration-sensitive metastatic prostate cancer is not recommended.

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