Present and future role of bisphosphonates in treatment

Bone metastases are part of a spectrum of conditions based on dysregulated osseous metabolism. Metastatic cancer cells activate osteoclasts, both directly, by producing and releasing local humoral factors that result in osteoclast activation, and by activating osteoblasts, which in turn further affect osteoclast activity. Activated osteoclasts, when uncoupled and unbalanced from osteoblast activity, result in net excess bone resorption, resulting in bone loss and eventually lytic or mixed metastatic lesions. Therefore, the osteoclast, and the humoral activation system that leads to osteoclast recruitment and activation have become the major targets for developing therapies active in bone metastases. Bisphosphonates are potent osteoclast inhibitors and interfere with recruitment of osteoclast precursors, activation and release of bone resorbing substances. Bisphosphonates represent the treatment of choice for osteoporosis. They might also have weak, but direct, antitumor effects. As single agents, bisphosphonates relieve pain, and reduce the skeletal complication rate associated with bone metastases. Prospective randomized trials have clearly demonstrated that when added to standard antitumor therapy, bisphosphonates reduce skeletal morbidity, fractures, pain and analgesic requirements, as well as the need for radiotherapy or orthopedic interventions. Bisphosphonates also increase the time to first skeletal event, thus extending the complication-free survival of patients with bone metastases. These observations have been made in a variety of tumor types. The optimal duration of bisphosphonate therapy has not been determined, and while the usual schedule of administration is monthly intravenous therapy for this indication, there are ongoing trials attempting to determine the most effective and safest schedule for patients with bone metastases. Similar studies are ongoing for patients with osteoporosis and osteopenia. Although bisphosphonates are very well tolerated, the last few years have brought a number of anecdotal reports of osteonecrosis of the jaw associated with bisphosphonate administration. More recently, systematic retrospective analyses of large databases have indicated a low but definite incidence of this complication, predominantly in patients receiving third-generation, potent bisphosphonates. These reports suggest the incidence to be in the range of 0.1–2.0%, varying with tumor type and research methodology. There is insufficient information about prevention and management of this condition, although risk factors include poor oral hygiene, oral/dental interventions, increasing cumulative dose of bisphosphonates and duration of therapy.

There is much interest and ongoing trials to define the role of bisphosphonates in the preventive treatment of primary breast cancer. Whether bisphosphonates can prevent osseous metastases or not, emerging information about their use in treatment-induced bone loss might lead to the incorporation of these agents into the combined modality management of primary breast cancer anyway. This makes the determination of therapeutic benefit, optimal dose and schedule of administration very important.