The result of inhibiting bone resorption is a net increase in bone mass. The ideal BpN is one that inhibits bone resorption without affecting bone mineralization. Aminobisphosphonates have these properties. The aminobisphosphonates most commonly in use at the present time are Pamidronate (Aredia O) and Alendronate (Fosamax O ). For the purpose of this discussion we will equate BpN's with aminobisphosphonates.

Therapeutic Applications
Osteoporosis
BpN's, as expected, would have their obvious indication in the treatment as well as prevention of osteoporosis. As there is a link between lack of estrogen and osteoporosis in women so also are there studies that show a relationship between a lack of testosterone and osteoporosis in men. Thus, BpN's should help prevent as well as correct osteoporosis in the PC population. We use Fosamax in our internal medicine patients to reduce the risk of fracture by increasing bone mineral density (BMD). A three-year study of 994 postmenopausal women from 16 countries found that the drug increased BMD of the spine by 8.8 percent; the neck by 5.9 percent; the thigh 7.8 percent; and overall by 2.5 percent. These increases in BMD were maintained for months following cessation of BpN treatment indicating superiority of BpN over estrogen or calcitonin. The risk of fractures was decreased by 48 percent.

The adverse effects with Fosamax are abdominal (6.6%) and musculoskeletal pain (4.1%). The dose of Fosamax is one 10 mg tablet taken with plain water 30 minutes before breakfast. Increasing the time before breakfast to 2 hours increases the bioavailability by 40%.

The prescription drug is about $60 per month, but most private insurance will cover the cost.

I would also supplement the biphosphonate with calcium citrate (1,000 mg per day given as 500 mg in the morning with breakfast and 500 mg at night before sleep) and vitamin D (Rocaltrol 0.5 micrograms per day- this is a prescription item). It is important that your doctor monitor blood calcium levels at intervals.

Recently, a calcitonin prescription drug that previously had to be injected also became available in a nasal spray. The spray is marketed under the name Miacalcin.

"The evidence of efficacy is based on increases in spinal bone mineral density observed in clinical trials. Two randomized, placebo controlled trials were conducted in 325 post-menopausal females--227 Miacalcin (calcitonin-salmon nasal spray)-treated and 98 placebo-treated with spinal, forearm or femoral bone mineral density (BMD) at least one standard deviation below normal for healthy premenopausal females. These studies, conducted over two years, demonstrated that 200 I.U. daily of Miacalcin (calcitonin-salmon nasal spray) increases lumbar vertebral BMD relative to baseline and relative to placebo in osteoporotic females who were greater than 5 years post-menopause. Miacalcin produced statistically significant increases in lumbar vertebral BMD compared to placebo as early as six months after initiation of therapy with persistence of this level for up to 2 years of observation. Nasal irritation, reported by 12 percent of the patients tested for the drug, and other symptoms such as dryness, redness, itching and bleeding were the most commonly reported side effects. Miacalcin costs about $60 a month and is covered by most private insurance. One recent review article suggested that the gains in BMD resulting from estrogen or calcitonin did not persist after treatment with either of these agents was discontinued. {Chow M. Focus on Alendronate. Formulary 31:23-30, 1996.}

Hypercalcemia of malignancy
There have been a number of medical articles showing the superiority of Aredia(pamidronate) over earlier bisphosphonate compounds (Didronel(editronate), Clodronate) in the treatment of hypercalcemia associated with malignancy. Aredia at a dose of 60 mg single 24 hour infusion was compared to Didronel at a dose of 7.5 mg/kg over 2 hours x 3 days. By day 7, 70% of the Aredia treated patients had normal corrected calcium levels compared to 41% of the Didronel treated patients. {Gucalp R, Ritch P, Wiernik PH et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 10:134-142, 1992. }

To evaluate dose response relationships using Aredia in the treatment of hypercalcemia of malignancy, one study used 3 different doses, 30 mg, 60 mg, and 90 mg as a single 24 hour infusion.

{Nussbaum SR, Younger J, VandePol CJ et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-60- and 90-mg dosages. Amer J Med, 95:297-304, 1993.}

Finally, studies have been done evaluating the infusion time of Aredia in patients with hypercalcemia of malignancy. 60 mg of Aredia infused over 4 hours vs 24 hours was compared to normal saline alone. By day 7, normal corrected calcium levels were seen in 78% of the 4 hour infusion group compared with 61% of the 24 hour infusion Aredia group. Calcium levels returned to normal in 22% of the patients infused only with saline. {Gucalp R, Theriault R, Gill I et al. Treatment of cancer-associated hypercalcemia. Arch Int Med 154:1935-1944, 1994.}

Bone pain
We use Aredia (Pamidronate) intravenously to help with bone pain in patients with metastatic PC. We use an oral formulation of Fosamax (Alendronate) to maintain the results of Aredia. Aredia is not available in oral form nor Fosamax in intravenous form in the United States. In a report by Clarke et al, Aredia was used in 25 patients with PC and bone pain. Patients received 30 mg of Aredia weekly times 4 and then every other month. Eleven out of 17 patients with pain at the start of the study were pain free at the end. In addition, fasting morning calcium excretion fell and serum osteocalcin decreased during Aredia therapy. Hydroxyproline excretion in the urine fell in 13 of 20 evaluable patients. These laboratory trends are indicators of positive calcium metabolism and reflect a decrease in bone resorption. In some patients bone scans stabilized and PAP levels decreased. Unfortunately, the authors did not measure PSA. {Clarke NW, Holbrook IB, McClure J & George NJR. Osteoclast inhibition by Pamidronate in metastatic prostate cancer: a preliminary study. Br J Cancer 63:420-423, 1991.}

Bone metastases
BpN's have a potentially exciting role in the management of prostate cancer (PC) patients. BpN's may also help in preventing PC grow in bone. This hypothesis is based on a rat model of breast cancer involving human breast cancer cell lines. These studies showed that a BpN called Risedronate decreases tumor burden in mice with a breast cancer that usually metastasizes heavily to bone. In all experiments, "Risedronate either inhibited the development of new bone metastases or slowed progression of already established bone metastases. The tumor burden in bone was significantly diminished with Risedronate. Furthermore, mice that underwent treatment continuously with Risedronate showed significantly longer survival than did control mice." It appeared unlikely that Risedronate has direct anti-cancer effects since the volume of cancer that had metastasized to soft tissues in the surrounding bone was not decreased in Risedronate treated animals. The authors emphasize that in their animal model the drug was given "from the beginning of cancer cell inoculation or in a prophylactic manner. It is, therefore, possible that prophylactic administration of the bisphosphonates to cancer patients with high risk of bone metastasis might not only be preventive but prolong survival." {Sasaki A, Boyce BF, Story B, et al: Bisphosphonate Risedronate reduces metastatic human breast cancer burden in bone in nude mice. Ca Res 55:3551-3557, 1995.}

The theory behind the above is that osteoclasts( the cells that break down bone) release growth factors or cytokines in the process of bone turnover. These growth factors may provide a favorable microenvironment for PC to set up house in the bone. These cytokines are identical or similar to those that are involved in tissue repair mechanisms and in the growth of tumor cells. BpN's inhibit bone turnover by stopping osteoclast formation, access or activity in bone and may therefore be not only helping osteoporosis but also preventing bone metastases from occurring or decreasing the growth rate of established bone metastases.

In a rat model of PC, the bisphosphonates Clodronate and Pamidronate were shown to delay the effects of skeletal metastasis in comparison to a placebo treated group. Bisphosphonates would appear to be reasonable candidates to use in combination with other anti-cancer treatments in the initial management of malignancies with a high predilection for bone metastases. {Yu-cheng S, Geldof AA, Newling DW, et al. Progression delay of prostate tumor skeletal metastasis effects by bisphosphonates. J Urol 148:1270-1273, 1992.} This is extrapolation of mouse data based on breast cancer and not PC. Therefore please do not conclude that this is occurring-it needs clinical studies to confirm this. These optimistic hypotheses must be balanced by the concerns that bisphosphonates may increase tumor volume in non-bone sites. One study using a similar mouse animal model as Sasaki et al described the outgrowth of cancer cells from bone into surrounding soft tissue through bone foramina of the external venous plexus. {Arguello F, Baggs RB, Duerst RE et al. Pathogenesis of vertebral metastasis and epidural spinal cord compression. Cancer 65:98-106, 1990} Further studies and clinical trials in the use of biphosphonates in prevention and treatment of malignancies with a high predilection for bone are warranted.

Cytokine = one of many growth factors important to cellular function

Endogenous = inherent naturally to the organism 

Hydroxyapatite = a crystal structure that is a building block for bone

Hypercalcemia = abnormally high concentrations of calcium in the blood 
indicating leeching of calcium from bone    

Hypocalcemia = low blood calcium; symptoms may include irritability, muscle 
spasms or contractions of hands, feet or legs

Osteoclast = cell that breaks down bone--cell grows in bone tissue and 
apparently absorbs bone tissue, Pac-man fashion

Phagocytosis = ingesting of a substance within a cell