What Are Bisphosphonates and how do they work?

Bisphosphonates are analogs of a naturally occurring compound, pyrophosphate, and are drugs that prevent bone breakdown.  

Bisphosphonates are drugs that suppress or reduce bone resorption by osteoclasts, i.e., they either directly kill the osteoclast cells or prevent/hinder them from removing bone. They may also act indirectly by stimulating the bone-forming cells(osteoblasts) to produce a substance that inhibits osteoclast formation. Unfortunately, although they can be effective for relieving bone pain, they do not provide a cure.

The following applies to FDA approved drugs (USA).

Bisphosphonates Approved for Osteoporosis

Alendronate, trade name: Fosamax® (Merck).

Fosamax has been shown to increase BMD and decrease fracture incidence in men with osteoporosis and has been approved by the FDA for the treatment of men with osteoporosis.

Risedronate, trade name: Actonel® (Procter & Gamble/ Aventis)  

Bisphosphonates Approved for Cancer-Related Conditions
 

- Hypercalcemia of Malignancy.

- Treatment of patients with multiple myeloma.

- Bone metastases from solid tumors in conjunction with standard anti-cancer therapy.

Prostate cancer patients should have failed to benefit from continuing treatment with at least one hormonal therapy.

A test of kidney function is needed before each infusion of Zometa® since it has not been established that Zometa® can be safely administered if kidney function is not normal. To emphasize the importance of checking the patient's creatinine before infusing Zometa, see the recent paper by William Oh, et al.

William K. Oh et al, The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid, Cancer, Volume 109, Issue 6 , Pages 1090 - 1096. "Renal impairment was observed in 23.8% of patients. The risk of renal impairment increased with an extended duration of zoledronic acid therapy

(<6 months, 11.1%; 24 months, 26.3%) and previous pamidronate treatment

(45.5% vs 19.0% for patients with no prior pamidronate). A significantly

greater risk of renal impairment was associated with increasing age at

zoledronic acid initiation, prior pamidronate use, and a history of renal

disease, hypertension, or smoking (P 0.05)."  See the prescribing information for creatinine requirements.

Osteoporosis.  Zometa is effective at preventing osteoporosis, even with extended intervals between infusions. 

One 4mg treatment of Zometa, once/year has been shown to be sufficient for preventing osteoporosis(but is not approved for that purpose.)  A clinical trial using 5mg once/year in post-menopausal women with osteoporosis, showed fewer fractures than the placebo group (hence effective for combating osteoporosis.) Their conclusion was, "A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures."  A higher incidence of serious atrial fibrilation was seen in those receiving Zometa (see Dennis M. Black, et al, Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis, The New England J. of Medicine, Volume 356:1809-1822 May 3, 2007 Number 18.)

Pamidronate, Trade Name: Aredia®(Novartis)

Zometa®(zolendronic acid for injection)
 

Zometa is covered here in detail, as it has been specifically approved for bone metastases in hormone-refractory prostate cancer.

Note: Zometa is given by infusion(IV). Fifteen minutes is the minimum time for this infusion.  Longer times -- as long as 30-60 minutes may be better for you.  A number of Zometa users have experienced significant pain following the prescribed 15-minute infusion. One patient describes his pain as a severe joint pain, even in the fingers, that put him out of commission for 2-3 days.  This man’s oncologist began questioning his other patients who used Zometa and found that 50% of them were also experiencing the same side effect. Most of the patients have overcome this problem by the simple expedient of stretching out the infusion period to 30-60 minutes.  All who have done this and discussed it on our support list have been successful in completely eliminating the problem.

Another potential problem is an acute phase reaction (a flu-like symptom) on the first infusion which can be avoided by reducing the initial dose to 1-2mg and then increasing to 4mg on the next dose.  Tylenol taken after the infusion may also help with the pain.

Novartis, the manufacturer of Zometa®, recommends that a multiple vitamin with 400 IU vitamin D along with an oral calcium supplement of at least 500mg be taken once a day while on Zometa.

Introduction

FDA approval of Zometa is for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy, i.e., hormone refractory prostate cancer/androgen insensitive prostate cancer.

Phase III Trial Results.   What Were the Results from the Phase III Trial on Men with HRPC? This is covered in the paper by Fred Saad, et al².  

Three phase III trials of Zometa® were run, one of which was for hrpc patients. The end point was the proportion of patients with skeletal related events(SREs) defned as having either a pathologic fracture, radiation therapy or surgery to bone, spinal cord compression or (for hrpc only) change in chemotherapy due to increased pain.

• 039 - placebo controlled, randomized HRPC trial. 4mg vs 8mg vs placebo. 643 patients randomized to the 3 arms and all but 7 had at least one bone metastasis. The primary efficacy study was the proportion of patients having at least one SRE. Zometa or placebo were given every 3 weeks for 15 months.

Note: Of course SREs arise from bone metastases. Secondary end points were time to 1st SRE, proportion of patients with individual SREs, time to disease progression, objective bone lesion response, bone biochemical markers and quality of life parameters.

• 011 - placebo controlled, randomized solid tumors but not breast or prostate cancers, 4mg vs 8 mg vs placebo.

• Breast cancer and myeloma, Zometa 4mg or 8 mg vs pamidronate 90mg.  No placebo.

Changes made from start of the trials to conclusion were: 5 minute infusions increased to 15 minutes and 8 mg dose of Zometa was reduced to 4mg.  The reason was renal(kidney) toxicity. 

Results of 039.

Skeletal-Related Events(SRE) and time to 1st SRE.

Bone Lesions(metastases).

- complete response defined as resolution of all osteoblastic metastases and complete recalcification of all osteolytic metastases.

- partial response defined as the resolution of some, but not all osteoblastic metastases or a decrease of at least 50% in the size of measurable osteoblastic mets and a decrease of at least 30% in the size of evaluable osteoblastic metastases, or at least partial recalcification of one or more osteolytic metastases and no new bone metastases or progression of any metastasis.

- stable bone metastases, no change.

Other Parameters

a. no statistical difference among the 3 groups.

b. no statistical difference among the 3 groups for percent change from baseline serum PSA within 30 days of progression of disease. Therefore, Zometa had no apparent effect on the secretion, clearance or measurement of PSA.

c. no statistical difference among the 3 groups.

Adverse Events

The most frequent adverse events are listed in the following table gives the per cent of patients with adverse events in each treatment group. The events listed are those that occurred in at least 5% more patients on Zometa than in the placebo group. For example, bone pain, not listed, occurred in 50.5% of the Zometa 4mg patients, but occurred in 61.1% of the placebo patients.

# Myalgia: the pain or discomfort involving any muscle(s) -- muscle pain. Myalgia can be generalized muscle pain.

## Arthralgias(joint pain) and pyrexia(fever), electrolyte disturbances and hypocalcemia were also seen, but did not require stopping treatment.  May be a characteristic of bisphosphonates.³

Refer to the paper by F. Saad, et al² for a more detailed discussion of adverse events.  

Comments

The 8mg/4mg results, for the most part, fall in between the placebo and 4mg groups and weren't statistically different from the placebo group. While the reason for this is "unknown", the paper suggests that the 8mg/4mg results may reflect that the 4mg dose is exerting the maximum effect on bone cells.

Additionally, the men entering this study were not evaluated for bone mineral density before the trial and hence may have been already had osteoporosis to begin with (hence more susceptible to fractures.) The trial, therefore,  did not distinguish between fractures from osteoporosis and from metasatic disease.  However, an SRE characterized by the need of radiation, spinal cord compression, surgery to bone or change in antineoplastic treatment should be metastatic disease specific.

The bone turnover can also separate bone mineral density concerns from metastatic lesion concerns considering that: metastatic lesion turnover > LHRH(or orchiectomy) turnover > women's "classical" osteoporosis turnover.

New News

7 January 2008.  The US FDA has posted an alert pertaining highlighting the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. This is different from the acute phase reaction.

For more information see the following pages

http://www.fda.gov/cder/drug/InfoSheets/HCP/bisphosphonatesHCP.htm

As of October 17, 2002 Novartis has submitted a supplementary New Drug Application for Zometa. This covers treatment and safety data out to two years(Zometa had long-term efficacy and safety profile). 

Fosamax and Ketoconazole

Clinical trial data for Fosamax in hormone refractory men is limited.  One trial from the USA NCI is: A Randomized Phase II Study of High Dose Ketoconazole Plus Alendronate Versus High Dose Ketoconazole in Patients with Androgen Independent Metastatic prostate Cancer, Trial number  99-C-0052.

This was an open-label, randomized study in HRPC men and compared high-dose ketoconazole(HDK) with and without added Fosamax. HDK dose was 400mg 3x/day with 20mg hydrocortisone in the morning and another 10mg in the evening. Fosamax dose was 40mg/day.

AUA 2000 abstract #1165. Dahut et al, "A Randomized Phase II Trial of Ketoconazole (KT) and Alendronate (AL) versus High Dose Ketoconazole in AIPC," published the results of this small study which was still accruing patients at the time of the abstract -- hence these are early results.

Of 22 men, 12 got HDK, Hydrocortisone (HC) and AL (40mg/day), 10 of 12 were still in the trial, 5/8 (63%) evaluable men had PSA decline >50% while on the HDK/HC arm there were 11 and 6/11 remain on trial and 3/10(30%) evaluable men had PSA declines >50%.

So for the HDK/HC/Fosamax arm the RR was 63% vs the HDK/HC arm RR was 30%. 

Fosamax was also stated to block secretion of MMP-2 and "may" block establishment of bone mets in human PC3ML cells in SCID mice.(note the use of 'may' and 'mice.'

References and Links
 

1. Lipton A, Small E, Saad F, Gleason D, Gordon D, Smith M, Rosen L, Kowalski MO, Reitsma D, Seaman J., The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate," Cancer Invest 2002;20 Suppl 2:45-54.

2. Fred Saad, Donald M. Gleason, Robin Murray, Simon Tchekmedyian, Peter Venner, Louis Lacombe, Joseph L. Chin, Jeferson J. Vinholes, J. Allen Goas, Bee Chen, "A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory Metastatic Prostate Carcinoma,"  Journal of the National Cancer Institute, Vol. 94, No. 19, 1458-1468, October 2, 2002.

3. Cohen MH et al, "US Food and Drug Administration Drug Approval Summary: Imatinib Mesylate, Mesna Tablets and Zoledronic Acid," The Oncologist 2002;7:393-400.