Cancer, Cancer Treatment, and Bone Health
Cancer and Bone Health
This issue has been studied incompletely. To our knowledge, only in patients with multiple myeloma has a generalized loss of bone density been observed (probably as a result of cytokines, such as interleukin 6, stimulating bone reabsorption,).[44] In general, cancer may influence bone health through at least three mechanisms: metastases, which increase bone fragility, especially osteolytic metastases; paraneoplastic syndromes associated with increased concentrations of PTH-like peptide and bone reabsorption[45]; and general malnutrition.[46]
The paraneoplastic production of PTH-like peptide and malnutrition are generally short-lived and do not have a significant effect on the risk of fractures. More information is needed regarding the bone density of patients with advanced cancer, especially those with bony metastases only, who may live several years following diagnosis and be at risk of fragility fractures.
Hormonal Treatment of Cancer and Bone Health
The effects of hormonal treatment on bone health have been best studied.
Chemical castration of men with prostate cancer via administration of luteinizing-hormone releasing-hormone (LHRH) analogs for 1 year and longer has been associated with a progressive increase in the risk of fractures.[47-49] The overenthusiastic use of this practice has led to a number of unnecessary complications, including osteoporosis in otherwise healthy men.
The benefits of androgen deprivation have been conclusively established in the management of patients with evidence of metastases on imaging[50] and in patients receiving radiation therapy for locally advanced disease.[51,52] In the meantime, it is clear that primary hormonal treatment of localized prostate cancer does not reduce the death rate of these patients; is associated with serious complications, including hot flushes, osteoporosis, diabetes, and coronary artery disease; and should be discouraged.[49,53]
Other areas of hormonal treatment are controversial. These include adjuvant hormonal treatment in the presence of positive lymph nodes after prostatectomy[50,54,55] and hormonal treatment of recurrences of pure prostate-specific antigen (PSA) level increases.[56]
The complications of androgen deprivation in the majority of situations may be prevented by:
• Limiting androgen deprivations to patients for whom this treatment is clearly indicated, or for whom there is evidence of rapidly growing tumor as indicated by short PSA doubling time;
• Use of intermittent androgen blockade in lieu of continuous blockade[57];
• Use of an estrogenic preparation. Until the advent of LHRH analog, estrogens(Drug information on estrogens) were the mainstay for management of metastatic prostate cancer. Although these products were associated with increased risk of deep vein thrombosis and fluid retention, they had significant advantages over the LHRH analog, including absence of hot flushes, decreased incidence of loss of libido, and bone preservation. While the dose of common use in the US (diethylstilbestrol at 3-mg daily) had an unacceptable complication rate, lower doses may be equally effective and less toxic. For example, a recent British study found promising results with transdermal estrogen patches[58]; and
• Concomitant treatment with zoledronic acid(Drug information on zoledronic acid)[42] or denosumab.[43] It must be emphasized, however, that these compounds have not yet been proven to reduce the risk of fractures.
Current hormonal treatment of breast cancer has also been associated with increased risk of osteopenia, osteoporosis, and bone fractures. This includes estrogen deprivation in premenopausal women[59] and aromatase inhibitors in postmenopausal women.[60,61] Bone complications in these patients may be prevented as follows:
• Use of tamoxifen(Drug information on tamoxifen) in lieu of aromatase inhibitors in postmenopausal women or sequential use of a SERM and an aromatase inhibitor[61]; and
• Concomitant treatment with a bisphosphonate[59,62-64] or denosumab.[65] While these agents proved effective in preventing bone loss, there is no proof as yet that they may also prevent bone fractures. A titillating possibility suggested by some of these studies is that bisphosphonates also may prevent recurrence of breast cancer. This hypothesis is being tested in ongoing trials.[66]
Cytotoxic Chemotherapy and Bone Health
The effects of cytotoxic chemotherapy on the bones are less known and deserve to be studied, especially in older patients.
It is well known that chemotherapy-induced early menopause has been associated with an increased incidence of bone loss.[62,66] Likewise, in young men with non-Hodgkin's lymphoma and chemotherapy-induced hypogonadism, Holmes et al found decreased bone density,[67] compared with age-matched controls. Strictly speaking, however, these are not direct consequences of cytotoxic chemotherapy.
Skeletal complications of cancer treatment have been extensively reviewed by Stava et al.[5] With the exception of growing children, in whom growth retardation is expected, there is no clear evidence that cytotoxic agents cause bone loss, despite a number of animal studies supporting this possibility.
Reviewing Surveillance, Epidemiology, and End Results (SEER) data, Cabanillas et al found that the risk of bone fractures and osteoporosis was two-fold higher among patients aged 65 years and older who had received chemotherapy for non-Hodgkin's lymphoma, compared with those who did not. Prior to administration of chemotherapy, the risk was comparable for these two groups.[68] In contrast, Brown et al compared the bone density of 115 male patients younger than 70 years of age who had received chemotherapy for testicular cancer and lymphoma against that of 102 age-matched controls, and found no differences between the two groups.[69]
While it is clear that chemotherapy-induced hypogonadism is associated with osteoporosis, limited clinical data support the possibility that osteoporosis could be a direct effect of cytotoxic chemotherapy. Older individuals may be at increased risk for this complication, however, and should be studied prospectively.
Conclusions
With the exception of multiple myeloma, there is no clear indication that cancer is associated with decreased bone density and mineralization, although it is well established that lytic bone metastases are a common source of pathologic fractures. The best-established effects of cancer treatment on bone density concern hormonal treatment of prostate and breast cancer. Androgen deprivation for longer than 1 year has been associated with an increased risk of fractures. Bone loss may be prevented with a more limited use of therapeutic castration, with the substitution of therapeutic castration with estrogen, and with concomitant use of bisphosphonates or denosumab.
Postmenopausal women receiving adjuvant treatment with aromatase inhibitors are also at increased risk of bone fractures. Bisphosphonates and denosumab prevent bone loss even in these patients, but the effect on fracture incidence is still unknown.
Recent analysis of the SEER data suggests that cytotoxic chemotherapy may decrease bone density and increase the risk of fractures in persons over 65 years of age. Given the prolonged survival of many older cancer patients, and the availability of agents capable of ameliorating osteoporosis, this issue deserves to be addressed in prospective studies.
Financial Disclosure: Dr. Balducci serves on the speakers bureau of, and has received research funds from, Amgen.
