
Usually bone metastases are lytic lesions, ones in which the bone is destroyed and replaced with tumor tissue. Lytic lesions imply an increase in osteoclastic bone cell activity.  Tumor cells within the bone marrow space can secrete substances [paracrine factors] that stimulate osteoclast function, resulting in osteolysis [bone destruction].  Also, bone cells can release cytokines and growth factors, which might can encourage tumor growth.

Bisphosphonates, a class of drugs that inhibit osteoclast activity, are useful in preventing and/or inhibiting the growth and symptoms of lytic bone metastases, as well as preventing and treating generalized osteoporosis [sometimes caused by chemotherapy agents] in cancer patients.

 " All bisphosphonates are characterized by a phosphorus-carbon-phosphorus (P-C-P)-containing central structure, which promotes their binding to the mineralized bone matrix, and a variable R' chain which determines the relative potency, side effects, and probably also the precise mechanism of action. Following administration, bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclasts leading to very high local concentrations of bisphosphonate in the resorption lacunae (up to 1,000 µM). On release from the bone surface, bisphosphonates are internalized by the osteoclast, where they cause disruption of the biochemical processes involved in bone resorption [9]. Bisphosphonates also cause osteoclast apoptosis, with the appearance of distinctive changes in cell and nuclear morphology. Although the molecular targets responsible for promoting this apoptosis are unknown, the bisphosphonates have recently been shown to inhibit enzymes of the mevalonate pathway which are ultimately responsible for events that lead to the post-translational modification of GTP-binding proteins such as Ras. Recent studies also suggest that bisphosphonates may have direct apoptotic effects on tumor cells [10, 11]. "  &&url 


<b>Use of Bisphosphonates

Bisphosphonates for Hypercalcemia of Malignancy</b>
Hypercalcemia is a common complication of malignancy.  Focal bone destruction by tumor cells, generalized bone destruction by substances secreted by the tumor, and impairment of kidney function may all contribute to high blood calcium levels. Intravenous bisphosphonates are now established as the treatment of choice for hypercalcemia [too high a level of calcium in the blood]. Seventy to ninety percent of patients will achieve normocalcemia resulting in relief of symptoms and improved quality of life [12] 

<b>Bisphosphonates for Bone Pain</b>
Radiotherapy is the treatment of choice for localized bone pain but many patients have widespread poorly localized, nonmechanical bone pain while others will experience recurrence of pain in previously irradiated skeletal sites. The bisphosphonates provide an alternative treatment approach to the management of these patients. [13-15].

<b>Randomized controlled trials of intravenous pamidronate, clodronate, ibandronate, and zoledronate have all demonstrated bone tumor pain relief.  None of the oral preparations alone have been shown to reduce bone tumor pain.</b>  Both sclerotic and lytic lesions respond to the bisphosphonates.  Bone tumor pain seems to be linked to the rate of bone resorption.   Patients with bony tumors and high rates of bone resorption respond poorly to bisphosphonates.  Following bone resorption markers will probably become important in evaluation the effects of bisphosphonate treatment.  [13, 16, 17]

<b>Bisphosphonates as Adjunctive Therapy in Metastatic Bone Disease</b>
Trials of bisphosphonates delayed disease progression in bone, and maintained quality of life and a reduction in pain and use of analgesics in treatment of breast cancer and multiple myeloma.  The research questions now are when to start treatment, optimal duration of treatment, and predicting those patients most likely to benefit.  Bisphosphonates may confer a small increase in survival time in the under 50 breast cancer group, and in myeloma patients receiving salvage chemotherapy. [1, 13-26]

 "We are still lacking good data from randomized trials of the role of bisphosphonates for other tumor types affecting bone. Osteoclast stimulation is a consistent finding in all tumor types, even those associated with predominantly sclerotic metastases, and certainly acute pain relief is seen in prostate cancer. However, at the present time long-term bisphosphonate use cannot be justified outside clinical trials until more evidence from the current trials is available." [12] 
 
<b>"Zoledronate [Zometa] is the most potent bisphosphonate in clinical development, and in in vitro systems has around 100-1,000 times the potency of pamidronate." [27,28]</b>

"Ibandronate is another highly potent amino-bisphosphonate which is licensed in Europe for the treatment of hypercalcemia of malignancy, and in late clinical development for both the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. "  An oral form has been developed. [14,29]

<b>Bisphosphonates as possible inhibitors of sarcoma and cancer cell growth</b>
"The bisphosphonate pamidronate is a potent inhibitor of Ewing's sarcoma cell growth in vitro "  "The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro." "Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro"

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<b>Bisphosphonates for Treatment of Osteoporosis</b>
Many patients with cancer are at increased risk of osteoporosis. This is a problem in women with uterine LMS, for whom there questions about the safety of hormone replacement therapy.  Chemotherapy can also precipitate osteoporosis.   Osteoporosis can be treated OR prevented with bisphosphonates.  [30]

<b>Bisphosphonates for Prevention of Bone Metastases</b>
There have been conflicting results in clinical trials testing whether bisphosphonates prevent bone metastases. [31-33]  Proving adjuvant effectiveness for bisphosphonates will need large randomized trials. Zoledronate, clodronate, and ibandronate are currently under investigation.   Significant positive results in preventing bone metastasis, added to the known effects of bisphosphonates on protecting bone mass, would make adjuvant treatment with bisphosphonates routine.   However, until results prove a benefit for their use, bisphosphonates  cannot be used adjuvantly except for the prevention  or treatment of osteoporosis.  [37]

<b>"The optimum time in the course of the disease to start bisphosphonates remains uncertain, but once treatment is initiated, patients should continue to receive bisphosphonate treatment for as long as the skeleton is the dominant site of metastases. Bisphosphonates may also prevent, or at least delay, the development of skeletal metastases and will prevent treatment-induced osteoporosis, but their routine use in early breast cancer cannot be recommended until the completion of confirmatory trials."[37] </b>

<b>Other Osteoclast Inhibitors </b>
"In recent years much has been learned about the signaling mechanisms between osteoblasts and osteoclasts and the control of bone metabolism in cancer. Osteoprotogerin (OPG) is a member of the tumor necrosis factor receptor superfamily which is a natural inhibitor of osteoclast production and activity. OPG acts as a decoy receptor binding with OPG-ligand, the natural stimulator of osteoclast maturation that is produced in large quantities by the osteoblast [34]. OPG has recently been shown to inhibit cancer-induced bone destruction and reduce skeletal pain in mice [35], and a synthetic version is now entering phase I trials in cancer patients. If the effects on bone resorption that have been seen in normal volunteer testing (Amgen-data on file) are confirmed in a cancer population, this long-acting subcutaneous preparation could be of great importance in the future. "[37]

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