Bisphosphonates are used as primary therapy for skeletal disorders characterized by excessive or imbalanced skeletal remodeling, leading to excessive osteoclast-mediated bone resorption and that also includes Paget disease of bone, malignancies metastatic to bone, multiple myeloma, and hypercalcemia of malignancy.
Mechanism of Action: Bisphosphonates attach to hydroxyapatite binding sites on bony surfaces. When osteoclasts (impregnated with bisphosphonate) begin to resorb bone that, the bisphosphonate released during resorption impairs the ability of the osteoclasts to form the ruffled border, to adhere to the bony surface, and to produce the protons necessary for continued bone resorption. Bisphosphonates also promotes osteoclast apoptosis.
CLASSIFICATION OF BISPHOSPHONATES
 Non–nitrogen-containing bisphosphonates also called as 1st Generation Bisphosphonates which are described as short chain molecules which inhibit the Krebs cycle.
The non-nitrogenous bisphosphonates are metabolised to form a non-functional molecule competeing with ATP in the cellular energy metabolism thereby osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.
 Nitrogenous bisphosphonates (also 2nd and 3rd Generation). The mechanism by which nitrogen-containing bisphosphonates promote osteoclast apoptosis is distinct from that of the non–nitrogen-containing bisphosphonates. They act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-CoA reductase pathway (also known as the mevalonate pathway).
- Zoledronic acid
Oral Bisphosphonates prepration allowing for once-weekly (alendronate or risedronate) or even monthly (ibandronate or risedronate) oral administration is available. IV preparations in common use are (pamidronate, ibandronate, and zoledronic acid).
|Oral Bisphosphonates||Intravenous Bisphosphonates|
Zoledronic acid is a bisphosphonate indicated for the treatment of (FDA):
• Hypercalcemia of malignancy. It is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (4.0 g/dL – patient albumin [g/dL]).
• Patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.
|Median time to Normocalcemia||Duration to Normocalcemia||% Acheiving Normocalcemia|
|Zolendronic acid||4 days||32 days||87|
|Pamidronate||4 days||28 days||70-100|
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3. Purohit OP ct al. Br J Cancer 1 995;72: 1289-1 293
DOSING AND ADMINISTRATION
Imp Note > All patients should get dental evaluation prior to initiating therapy with an inhibitor of osteoclast function unless there are mitigating factors chat preclude a dental assessment to prevent ONJ (see below for details)
Approximately 10% to 30% of patients receiving their first nitrogen-containing bisphosphonate infusion will experience an acute phase reaction, most commonly characterized by transient pyrexia with associated myalgias, arthralgias, headaches, and influenza-like symptoms. (Premedicate with antihistamine + antipyeretic + steroid)
 Hypercalcemia of malignancy
• 4 mg as a single-use intravenous infusion over no less than 15 minutes.
• 4 mg as retreatment after a minimum of 7 days.
Initiate treatment only after:
- Adequate hydration with 0.9%NS.
- Adequate urine output of =2 L/d throughout therapy.
Dose adjustments of zoledronic acid are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to moderate renal impairment prior to the initiation of therapy (ie with SCr <4.5 mg/dL)
 Multiple myeloma and bone metastasis from solid tumors.
• 4 mg as a single-use intravenous infusion over no less than 15 minutes every 3-4 weeks for patients with creatinine clearance of greater than 60 mL/min.
Dosing > intravenously in 100 mL 0.9% NS or D5W over at least 15 miutes every 3-4 weeks (4 mg is recommended for patients with CrCl >60 mL/min)
Note > Coadminister oral calcium supplements of 500 mg and a multiple vitamin
containing 400 international units of Vitamin D daily.
Precautions while administration (1) Do not allow to come in contact with any calcium or divalent cation-containing solution eg Never Mix in Ringer Lactate soln (2) Do not administer zoledronic acid through a common intravenous line or the same ﬂuid pathway through which ocher drugs are being administered.
The International Myeloma Working Goup 2012 recommendations for the management of multiple myeloma-related bone disease: (Link here for Ref)
|Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography.|
|IV zoledronic acid or pamidronate is recommended for preventing skeletal-related events in patients with MM. Zoledronic acid is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits.|
|BPs should be administered every 3 to 4 weeks IV during initial therapy.
After 1 year of therapy
After 2 year of therapy
**2012 New recomendation > After 2 years continue if ≤ PR
So Now Zolendronate should be administered until disease progression, except in patients who have achieved CR or VGPR, for whom there are no data regarding the survival advantage of Zolendronate.
|Should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response.|
Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression.
|Choice||Zolendronate (first option)|
|Pamidronate (second option)|
|Clodronate (only in patients who cannot come to hospital, those with severe disabilities, and those with contraindications to Zolendronate or Pamidronate)
Note Oral Clodronate is contraindicated if CrCl is < 12 mL/min.
Dose Adjustents for CrCl < 60 mL/min
|Pre-Treatment Creatinine||Recomended Dose|
|50-60 mL/min||3.5 mg|
|40-49 mL/min||3.3 mg|
|30-39 ml/mn||3 mg|
Use not recomended if creatinine clearance <30 ml/min.
During treatment, serum creatinine should be measured before each Zometa dose and treatment should be witheld for renal detoriation. ie as follows
If baseline creatinine normal , increase of 0.5 mg/dL
If baseline creatinine abnormal, increase of 1.0 mg/dL
Withhold zoledronic acid until SCr decreases to within 10% of baseline, then resume with the same dose given previously.
Early diagnosis of renal Impairment is crucial, and urinary albumin and serum electrolytes in addition to CrCl rates should be monitored in these patients.
Adverse Events with Zolendronate
|Frequency||Adverse Events with Zolendronate|
|> 10%||Fever (30-40%), nausea/vomiting (29%), constipation (26.7%), hypomagnesemia ( 10.5%), hypotension (10.5%)|
|1-10%||Bone/back pain (10%), flulike syndrome, injection site reaction, dyspepsia, hypocalcemia, hypophosphatemia, hypermagnesemia, increased serum creatinine.|
|<1%||Rash, pruritus, increased liver transaminases, chest pain, ocular inflammation, osteonecrosis of jaw|
Ref: Zometa (zoledronic acid) Injection product label, October 2009 (revised). Novartis Pharmaceuticals Corporation, East Hanover, NJ
Some Important Complications – Review
 Osteonecrosis of the Jaw
ONJ is an uncommon but potentially serious complication associated with the use of bisphosphonates. Associated risk factors are poor oral hygiene, a history of dental procedures or denture use, and prolonged exposure to high IV bisphosphonate doses.
Nearly all ONJ cases (94%) have been described in patients receiving high doses of IV bisphosphonates (primarily zoledronic acid and pamidronate) for oncologic conditions. Prevalence in patients with myeloma ranged from 7% to 10%. (Ref Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws [published correction appears in Ann Intern Med. 2006; 145(3):235] Ann Intern Med. 2006;144(10):753–761.)
Reduced dosing schedule in patients with myeloma, in which IV bisphosphonate was given monthly for 1 year and then every 3 months thereafter, was shown to decrease the incidence of ONJ compared with monthly bisphosphonate infusions. (Ref: Corso A, Varettoni M, Zappasodi P, et al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia. 2007 Jul;21(7):1545–1548.Epub 2007 Apr 5. )
Zolendronate has been associated with a higher reported rate of ONJ than other BPs, and the cumulative dose and duration of therapy are believed to contribute to the development of ONJ.
Prevention of ONJ (FDA-UPDATE committee)
- Dental examination and necessary preventive dentistry prior to initiating therapy.
- Maintain optimal oral hygiene (ie brushing and ﬂossing teeth after meals and use of a ﬂuoride mauth rinse) and if possible, avoid invasive dental procedures that involve manipulation of the jawbone or periosteum.
- IMWG panel 2012 consensus is to stop BPs for 90 days before and after invasive dental procedures (eg, tooth extraction, dental implants, and surgery to the jaw). BPs do not need to be discontinued for routine dental procedures, including root canals.
 A FDA Alert issued in January 2008 highlighted the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates and we should be aware for that. Severe musculoskeletal pain my occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution.
Some other intresting points
Statins are another class of drugs that inhibit the HMG-CoA reductase pathway like Nitrogen containing bisphosphonates. Unlike bisphosphonates, statins do not bind to bone surfaces with high affinity, and thus are not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture (an indicator of osteoporosis) and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment of osteoporosis remains controversial. (Ref: Uzzan, B; et al. (2007). “Effects of statins on bone mineral density: a meta-analysis of clinical studies”. Bone. 40 (6): 1581–7. doi:10.1016/j.bone.2007.02.019)
Other indications of Zolndronate use
 Treatment of osteoporosis in postmenopausal women = Zoledronic acid 5 mg every 12 months (up three doses in clinical trials).
 Prevention of osteoporosis in postmenopausal women = Zoledronic acid 5 mg every 24 months.
 Treatment to icrease bone mass in men with osteoporosis = Zoledronic acid 5 mg once annualy up to a total of 2 doses.
 Treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be using glucocorticoids for at least 12 months (7.5 mg of prednisone or equivalent or more per day) = Zoledronic acid 5 mg
 Hypercalcemia of Malignancy = The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60 mg and 90 mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection. This infusion solution is stable for up to 24 hours at room temperature. (Longer infusion may reduce risk of nephrotoxicity)
*There are no controlled clinical trials comparing the efficacy and safety of 90 mg pamidronate disodium over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90 mg pamidronate disodium over 24 hours is similar to those who received 90 mg pamidronate disodium over 2 hours.
 Osteolytic Bone Lesions of Multiple Myeloma = The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection, and administered over a 4 hour period on a monthly basis.