It's my role to review the pathophysiology of bone diseases and specifically relate that to cancer treatments, including chemotherapy, hormonal therapy, and others.

We will begin by looking at bone remodeling.

As we sit here our bones are remodeling and it is estimated it takes about 36 months to replace our skeletons; about every 3 years you get a new inside and, fortunately, that holds you up.

Bone remodeling is characterized by 2 major activities: osteoblastic rebuilding of bone, and resorption of bone by osteoclasts.

Usually, these are interrelated; they are coupled and balanced. If we look at coupling, with normal bone osteoclast comes along and remodels the surface as it needs to; osteoblasts come in and rebuild the bone. The amount of bone removed is equivalent to the amount of bone replaced and they are anatomically distributed appropriately.

If they are coupled with imbalance, then there is either excessive osteoblastic activity or excessive osteoclastic activity, but the amount of bone made is the same; they are coupled but unbalanced.

A third possibility is uncoupled but balanced. You may have osteoclastic activity of the surface of the bone and make an osteoclastic lacuna at the bone, but then osteoblastic activity occurs at a remote site or not in the site necessary to replace the bone that has been removed.

The last possibility is uncoupled and imbalanced. This is the predominant phenomenon in cancer. You not only have excessive osteoclastic activity with destruction of bone, you have an imbalance in production of bone. You may have too much, in which case we have perhaps a radiographic appearance of osteoblastic disease, or you may have too little, in which case we have an appearance of osteolytic or osteoporotic bones. These are the 4 bone remodeling paradigms that one can think of as we look at bone remodeling in cancer.

A number of markers are available to measure whether there is a predominant osteolytic or osteoblastic component to bone disease. In osteoporotic bone disease, the primary event is degradation of bone and the biochemical markers of that include calcium/creatinine ratio and hydroxyproline/creatinine ratio, which are very rarely used, and perhaps the best is N-telopeptide, an amino terminal peptide of collagen crosslinks. C-telopeptide is also measured. These are all urine tests that can be ordered. At our institution we use N-telopeptide.

As serum markers, both N-telopeptide and C-telopeptide are available. Bone sialoprotein is measured at some sites. Markers of bone formation, osteoblastic activity, consist primarily of fractionation of the bone alkaline phosphatase measured in normal blood, and osteocalcin, which can be measured also in normal blood.

Breast cancer and prostate cancer have a lot in common. Women don't have prostates and most men don't get breast cancer; nevertheless, they have a lot in common. Primarily they cause bone metastases and that treatment results in a decrease in gonadal steroids, which results in decrease of bone mineral density. And decrease in bone mineral density results in increased fracture risk.

They also have in common the observation that hormone replacement therapy, giving women with breast cancer estrogen or men with prostate cancer testosterone, is relatively, if not absolutely, contraindicated. There are very limited prospective data on preventive measures for bone treatment, and treatment for bone loss as a consequence of metastatic disease or primary breast and prostate cancer.

What induces the bone loss? On the left is breast cancer. First is cytotoxic chemotherapy, and there are 2 mechanisms of cytotoxic chemotherapy inducing bone loss. First, there is a direct negative effect of the cytotoxic therapy on bone cells, predominantly osteoblasts and, second, many women who are premenopausal have cytotoxic therapy effects on ovarian function, which results in gonadal loss as well.

In addition, in premenopausal women, surgery (oophorectomy) or radiation therapy to the ovary, a good therapy in the adjuvant setting, also results in bone loss. Hormone therapy, tamoxifen in premenopausal women, and the aromatase inhibitors result in bone loss, as well as gonadotropin-releasing hormone (GnRH) antagonists/agonists, which shut off ovarian function. All of these result in estrogen depletion.

In prostate cancer, the list is nearly the same. Cytotoxic therapy again has a negative effect not only on testicular function but also on bone. Surgical therapy. Hormone therapy, including antiandrogens and GNRH agonists/antagonists, results in androgen depletion.

The final common pathway, estrogen and androgen depletion, is the result of bone mineral density being decreased.

In the bone microenvironment a lot of things are going on. There are both cellular functions and cytokine functions that help maintain bone integrity. Here we have a normal bone environment and we have pre-B cells, which produce receptor activator of nuclear factor-kappa beta ligand (RANKL). RANKL, when it binds to the receptor on osteoclasts, increases osteoclastogenesis, a recruitment from the monocyte and macrophage cell line of osteoclasts, and activates osteoclast precursors into active or mature osteoclasts, which then work on the site of bone and degrade the bone.

Osteoprotegerin, which is produced by osteoblasts, is in circulation and acts as a decoy receptor of RANKL. This is the inhibitory component to shut off osteoclastic function. Ordinarily there's a balance so that bones are remodeled and there's coupling and balance between function of osteoblasts and osteoclasts. This would be the normal bone microenvironment.

In an estrogen-depleted state, pre-B cells expand in number, activity of RANKL is increased, stromal cell production of RANKL is increased and, as a consequence, osteoclastic precursors and osteoclastogenesis are increased, resulting in more mature osteoclasts and excessive bone breakdown.

This is augmented by interleukin-6 production, which occurs as a consequence of estrogen depletion and may also occur as a consequence of prostaglandin E2, interleukin-1, and tumor necrosis factor alpha production, especially in metastatic disease to bone.

The consequences, bioavailable estradiol concentrations, are dramatically reduced. On the left are premenopausal women and the level is more than 200. Postmenopausal women levels are dramatically less. Even in men estradiol levels are higher until there is androgen depletion. So once androgen is depleted, once estrogen is depleted, that pathway of increased RANKL production, osteoclastogenesis, and osteoclast activation occurs.

Hypogonadism then occurs as a result of natural menopause, increased osteoclast formation, and survival, and leads to 5% to 10% loss of cortical bone within the first year to 2 years after menopause. Trabecular bone is lost at a greater percentage and trabecular bone, unlike cortical bone, is not reconstituted very well. Cancer treatment-related bone loss increases loss of cortical and trabecular bone both through the agents we talked about cytotoxic wise and because of hypogonadism.

In primary breast cancer, bone loss also occurs. Many women with primary breast cancer with estrogen-receptor positive tumors are treated with tamoxifen, and tamoxifen in the premenopausal woman results in bone loss, an opposite effect of what we see in postmenopausal women where bone integrity is maintained. Aromatase inhibitors, by inhibiting the conversion of androstenedione and testosterone to estradiol and estrone, result in further reduction in estrogen even in the postmenopausal woman. So if we look at the levels shown earlier in postmenopausal women, we will reduce it further, 90% or greater, with administration of aromatase inhibitors. This again increases osteoclastic activity.

Chemotherapy induces ovarian dysfunction that is related to the age of the patient, the type of drug administered, and the total dose of drug administered. If you are over 40 years of age and you receive 3 g of cyclophosphamide, there's a 90% probability you will become menopausal. If you are under 30 years of age and receive 3 g of cyclophosphamide, there's a 90% probability you will not, but if you receive 6 g of cyclophosphamide you will. So drug, dose, and age all impact chemotherapy induced ovarian dysfunction.

Last on our list we have ovarian ablation, which is still a very good treatment for primary breast cancer; it results in improved, disease-free, and overall survival. There are a number of methods to do this. Surgery, oophorectomy, is the standard, and has been around for a long time; radiation oophorectomy has also been around for a long time. The latest mechanism is the luteinizing hormone-releasing hormone (LH-RH) agonist/antagonist, which is very effective.

With bone loss in metastatic breast cancer, we have osteoclast activation by treatment, including the aromatase inhibitors, ovarian ablation, and chemotherapy. Chemotherapy has a dual effect, not only affecting ovarian function but also having a negative effect on the osteoblast. Tumor-induced bone loss is related to metastases and up to 80%, perhaps as many as 100%, of patients who develop metastases from primary breast cancer will have bone disease at some point in the clinical course of their disease. All of this results in excessive osteoclastic activity.

In terms of bone density in premenopausal women, if you measure lumbar spine bone loss, Shapiro showed that after 6 months of chemotherapy there was a 4% loss of bone density using a dual-energy x-ray absorptiometry (DEXA) technique in the lumbar spine. If you measured it after 12 months there was an additional 3.7% loss for a total loss of between 8% and 10% after 1 year of cyclophosphamide-methotrexate-fluorouracil (CMF) chemotherapy.

The implications for long-term breast cancer survivors, and fortunately we have many more of those women, are an increase in osteopenia and osteoporosis and an increase in fracture risk.

With oophorectomy, up to 20% loss of total bone mass may occur within 18 months. With goserelin, amenorrhea occurs in 95% of women who are premenopausal and, again, is attended by increased bone loss.

The gold standard for bone mineral density testing is DEXA. Early diagnosis and treatment of bone loss are essential. If we wait until there is fracture or a skeletal event, it's too late. The most sensitive test is DEXA. It is very accurate, more accurate than x-ray or computed tomography (CT) scan. It can be used to measure spine, hip, or total body bone density. There are also peripheral units to measure wrist, heel, and finger bone density as a screening tool.

For testing, one wants to detect osteopenia or osteoporosis before fracture. The lower the bone density, the greater the fracture risk. And once you've had fracture, it's too late.

Testing can also be used to determine the rate of bone loss by measuring serially bone mineral density at different time points; baseline, 6 months, 12 months, 2 years. And it can be used to monitor the effects of treatment, whether there's been improvement with whatever intervention we have chosen to use.

The World Health Organization criteria for bone loss use a T-score calculation. T score is the measure of bone in a young, normal person; young determined to be 30 years of age. It is considered to be the optimal or peak bone density. This will vary on the basis of population, race, and ethnicity but that is the normal. The difference between a patient's bone mineral density and that of a healthy young adult is the T score, and for every decrease in 1 standard deviation there's an increase in the relative risk of fracture of 1.5- to 2.5-fold.

Using these T scores, the World Health Organization has come up with criteria for bone loss to classify people as normal, osteopenic, osteoporotic, or severely osteoporotic. Normal means that your T score is within 1 standard deviation of the normal. Osteopenia is a T score that is -1.0 to -2.5. Osteoporosis is a T score of -2.5 or less (-2.6, -2.7, -3.1, etc). And severe osteoporosis means that you have a fracture.

The consequences of bone loss include fractured wrists, femurs, and vertebrae. Femoral neck fracture is the most devastating of the 3. Ten percent to 20% of patients require long-term hospital care, an additional 20% of patients require persistent assistance with daily living, and figures of 25% to 30% mortality within the first year of femur fracture are widely reported in the literature.

Vertebral fracture doesn't have the same mortality risk but it does result in chronic pain, skeletal deformity, loss of mobility, and loss of functional independence; it has a lot of comorbidity associated with it.

What treatments do we have for these things that occur as a consequence of our treatment for cancer? We can give calcium and vitamin D supplementation and there are standard recommendations about how much one should have. We usually use 1,000 to 1,300 mg/day of calcium. One can expect up to a 4% increase in bone mineral density.

Hormone replacement therapy, which recently has received a lot of bad press, is still a very effective therapy for osteoporosis, and it will increase bone mineral density.

Selective estrogen receptor modulators in postmenopausal women have an effect on bone density and maintain the integrity of bone, but are not very good at replenishing bone once lost. In this regard, raloxifene and tamoxifen are the 2 available.

Calcitonin can be used, and an intranasal preparation is approved for use in patients who are osteopenic.

Probably the most effective treatments are the bisphosphonates and listed here are alendronate and risedronate in yellow; they are commercially available oral preparations that are approved for the treatment of osteopenia and osteoporosis. The bisphosphonates differ in their potency and these are ranked in order of least to greatest potency, with oral clodronate being the least potent. Unfortunately, it's not available in the United States at present.

In randomized trials bisphosphonates have been shown to be superior to all other agents in increasing bone mineral density for those patients who have osteopenia or osteoporosis.

The rationale for intravenous (IV) bisphosphonate therapy in cancer treatment-induced bone loss has to do with the importance of maintaining bone health; primary prevention is better than secondary intervention.

Early-generation oral bisphosphonates have proven efficacy in prevention of osteoporosis but for some patients they are not the best. The oral agents are poorly absorbed, up to only 6% absorbed, and they require certain maneuvers, such as standing upright for a prolonged period of time after taking them. Occasionally they are associated with gastrointestinal toxicity, which may be severe.

Cancer treatment-induced bone loss is more rapid than the usual osteoporosis. Per Shapiro's data, within 6 months 4% of bone may be lost by bone mineral density. An effective treatment therefore may require a more potent agent, IV administered, than the oral agents.

There are also potential additional clinical benefits related to the potential reduction in risk of the development of bone metastases.

How do these work? We're going to focus on aminobisphosphonates because they have the greatest activity. They work in many ways, but there are 2 predominant ways. One is they block the accession of monocyte macrophage osteoclast precursors into osteoclastogenesis; instead of recruiting a lot of cells to become osteoclasts, that is blocked.

Secondly, mature osteoclasts, once they are active, have their function impeded by a number of mechanisms. One is this ruffled border where the cell kind of suction cups onto the bone is interrupted and cells cannot attach to bone very well. Intracellularly, liposomal activity of osteoclast is also inhibited and the low pH required at the cell surface for bone absorption is destroyed.

In addition, there are data showing that at least the aminobisphosphonates can result in osteoclastic cell apoptosis through activation of capsaicis.

Zoledronic acid is the most potent bisphosphonate we have, and it has an unusual structure. It's this heterocyclic diamino structure. There is a great deal of information indicating that structure function relationships exist with bisphosphonates, and this structure is important for the activity. It's considered a third-generation bisphosphonate, 100 to 850 times more potent than pamidronate using a rat model of hypercalcemia, and it has been shown to increase bone mineral density in postmenopausal women with osteoporosis.

In prostate cancer, it can prevent cancer treatment-induced bone loss.

These are from Reid's paper in the New England Journal of Medicine showing the difference in lumbar spine and femoral neck bone mineral density with the administration of zoledronic acid compared with placebo. Bone mineral density increases approximately 5% in lumbar spine and 2% in the femoral neck by 12 months after administration of zoledronic acid. So it has a very positive effect on bone mineral density in women with osteoporosis.

What can we conclude from this limited amount of information? Cancer treatment compromises bone integrity. Those treatments, including chemotherapy, surgery, radiation therapy, and hormonal therapy, all result in estrogen and androgen depletion and activation of osteoclasts. And activation of osteoclast results in bone destruction and increased fracture risk.

The size of this problem is not insignificant. In the 1990s, approximately 1.8 million women were diagnosed with breast cancer. Merely by being diagnosed with breast cancer, one is at increased risk of osteopenia and osteoporosis, and if one is diagnosed with metastatic breast cancer to bone, that risk is dramatically increased around 27- to 35-fold. One and a half million men were diagnosed with prostate cancer in the 1990s; 1.5 million men in all of our treatments that can result in bone loss, osteoporosis, and fracture risk. Because of this, there is a strong rationale for developing a potent IV bisphosphonate to prevent or to treat cancer treatment-induced bone loss.