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.
- 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 .
- 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.
- Hypercalcemia of malignancy.
- Bone lesions from multiple myeloma.
- Bone metastases from any solid tumor.
- 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
- IV use only, 4 mg/5 mL single-use vial of concentrate.to be diluted in 100ml normal saline infused no less than 15min.
- 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
- 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.
- 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
- 3mg ————CrCl=30-39ml/min
- not recommended if CrCl< 35ml/min
- Aminoglycosides: Hypocalcemic effects can be enhanced.
- NSAID: GIT and nephrotoxicity may be enhanced.
- Phosphate supplements: hypocalcemic effects of phosphate supplements can be enhanced.
- 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.
- 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
- 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 sodium is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption.
- 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
- 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.
- 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.
- 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.
- Atypical fractures
- 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.
- Available as 800 mg tablet each contains 1000 mg sodium clodronate tetrahydrate, equivalent to 800 mg anhydrous sodium clodronate.
- 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.
- 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|
- 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 is a fully human monoclonal antibody for the treatment of osteoporosis, treatment induced bone loss, bone metastases, multiple myeloma.
- 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.
- Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
- 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
- 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
- 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 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.
- 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
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.
- 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
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
- 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.