Bone Complications of Cancer Treatment in the Elderly

Osteopenia and osteoporosis are increasingly common in cancer patients, owing to the aging of the population and to new forms of cancer treatment. Androgen and estrogen deprivation, as well as some forms of cytotoxic chemotherapy, may lead to osteopenia and osteoporosis. Patients at risk for osteoporosis include those treated with aromatase inhibitors and with androgen deprivation for more than 1 year. In addition, all patients 65 years of age and older are at risk of osteoporosis when treated with cytotoxic agents, and so should be screened for bone loss. Several treatments have been effective in the prevention and management of osteoporosis. In patients at risk for this complication, it is recommended to obtain a bone density evaluation and to start appropriate treatment. This may include calcium and vitamin D supplementation for mild forms of osteopenia, and bisphosphonate therapy or denosumab (Prolia) for more advanced osteopenia and osteoporosis.

With the aging of the population, osteopenia and osteoporosis are becoming an increasingly common cause of morbidity, mortality, and health care costs.[1-3]

Given the increased survival of cancer patients, cancer treatment has become a major contributing factor to osteoporosis.[4-5] This long-term complication of cancer treatment is particularly relevant, as the majority of cancers occur in individuals 65 years of age and older who are already at risk for osteoporosis.[6] After a review of the pathogenesis of osteoporosis, this article examines the effects of common cancer treatments on the bones and explores a research agenda in this important field.

Osteoporosis and Osteopenia: Definition and Pathogenesis

Osteoporosis involves increased bone fragility resulting from decreased bone mass and microarchitectural distortion.[7-8] The diagnosis of osteopenia and osteoporosis is based on assessment of bone density by dual energy x-ray absorptiometry (DEXA) scan. According to the World Health Organization, one can identify four different situations with regard to bone stability:

• Normal bone, with a T-score higher than or equal to −1 SD;

• Osteopenia, indicated by a T-score between −1 and −2.5 SD;

• Osteoporosis, defined as a T-score lower than −2.5 SD; and

• Severe osteoporosis that involves one or more fragility fractures, in addition to a low T-score.

Fragility fractures are those occurring in the absence of recognizable trauma or as the result of a trauma that would not cause fractures of normal bones.

Central to the pathogenesis of osteoporosis is bone remodeling, a lifelong process that involves the reabsorption of old bone and the formation of new bone.[3,9] This takes place in the so-called bone remodeling centers (BRC),[9] which include the basic multicellular unit (BMU), the canopy of bone cells, and the blood vessels. The BMU consists of osteocytes, osteoblasts, and osteoclasts. Osteocytes are mechanosensors and trigger remodeling to adapt the bone to incoming and ongoing mechanical strains. The remodeling appears to start with the bone-lining cells that recruit osteoclasts to reabsorb the old bone, and these in turn stimulate a wave of new bone formation by the osteoblasts. Contrary to what was previously believed, the process of bone remodeling is essentially the same for the cancellous bone (the bone in contact with the marrow) and for the solid bone in the diaphysis of long bones. Osteoclasts originate from the pluripotent hematopoietic progenitors, and osteoblasts originate from mesenchymal cells. Osteocytes represent the final osteoblastic differentiation.

TABLE 1

Factors That Influence Bone Remodeling

A number of local factors maintain the balance of bone reabsorption and formation during bone remodeling. A detailed discussion of these factors is beyond the scope of the article. It is worth mentioning the best recognized among them, however, as they represent a target for the treatment of osteoporosis and may influence the growth of cancer (Table 1).

In the condition of homeostasis, the net result of remodeling on bone density is neutral. Osteopenia and osteoporosis occur when remodeling is altered by increased bone reabsorption, decreased bone production, or both.[3,9]

A variety of genetic, acquired, and environmental factors contribute to the pathogenesis of osteopenia and osteoporosis. Some genetic mutations have been associated with increased risk of osteoporosis,[10-13] but their impact in the general population is poorly understood.

Hormonal factors are perhaps the best understood. These include hypovitaminosis D, hyperparathyroidism, hypogonadism, and hypercorticism.

Vitamin D status is assessed by measuring the serum concentration of 25-hydroxyvitamin D, a precursor of the active compound, 1-25 dihydroxyvitamin D, that is synthesized in the kidney.[14] Consensus among experts is that levels lower than 20 ng/mL represent vitamin D deficiency. For the prevention of osteoporosis, levels higher than 40 ng/mL are desirable because these levels are necessary to inhibit excessive production of parathormone (PTH). Vitamin D deficiency leads to osteoporosis through at least two mechanisms: decreased intestinal absorption of calcium and phosphorus, and increased PTH secretion that is stimulated by declining levels of calcium. The importance of hypovitaminosis D in the pathogenesis of osteoporosis has been confirmed by randomized placebo-controlled clinical trials demonstrating a 29% reduction in vertebral fractures and 21% reduction in long bone fractures when 700–800 IU of 25-hydroxyvitamin D are administered daily together with 1,000–1,200 mg of calcium.[14]

PTH has a dual and somewhat antithetical role in the pathogenesis of osteoporosis. Low-dose and intermittent administration of this hormone causes formation of new bones, through stimulation of IGF-1 and other bone growth factors. Hyperparathyroidism, that is, consistently high circulating levels of PTH, is associated with increased bone reabsorption and osteoporosis.[3]

Estrogen decreases bone reabsorption in both women and men.[15-17] In randomized controlled studies, exogenous administration of estrogen or selective estrogen receptor modulators (SERMs) to postmenopausal women prevented, reversed, or delayed bone loss.[18] The effect of estrogen in men is not well known.

Testosterone prevents bone reabsorption after transformation into estrogen, and it may directly stimulate the formation of new bone.[19] An important study demonstrated that in elderly men treated with a gonadotropin releasing factor analog and with an aromatase inhibitor, the combination of estrogen and androgens was the most effective in preventing bone reabsorption, but estrogen alone was more effective than androgen alone in achieving this end. Androgen alone stimulated the release of osteocalcin, a protein produced by mature osteoblasts.[19] While the association of androgen deprivation and osteoporosis is well known, it is not clear whether androgen replacement may prevent or reverse this complication.[20-22] There are some important differences between osteoporosis in men and women that may reflect differences in the hormonal milieu.[21,23] In women, osteoporosis involves mainly a loss of trabecular number and space; in men, it results from a loss of trabecular thickness. Clinically, hip fractures in men are associated with a higher risk of death than in women.

The association of corticosteroids and osteoporosis is well known.[3,24] The mechanism of corticosteroid-induced bone loss includes the antianabolic effect of these hormones, as well as increased bone reabsorption and reduced vitamin D activation. Both activated vitamin D analogs (calcitriol and alfacalcidol)[25] and bisphosphonates[26] may ameliorate corticosteroid-induced osteoporosis.

Other factors that may influence bone density include protein-calorie malnutrition, excessive alcohol intake, smoking, and medications.[27] Three associations are of special interest to the readers of this article: the association of osteoporosis with hypomagnesemia, with proton pump inhibitors (PPIs), and with frailty. Hypomagnesemia is often nutritional in origin,[28] but a number of drugs, including platinum derivatives and anti-epidermal growth factor receptor (EGFR) antibodies, may cause urinary loss of magnesium. Other possible mechanisms of hypomagnesemia include malabsorption and hypoparathyroidism. This condition is associated with decreased calcium availability and secondary hyperparathyroidism, both of which may lead to osteoporosis. The association between osteoporosis and PPIs was recently described.[29] The exact size of this association, as obtained from two large population studies,[29] is difficult to estimate, as the majority of people involved had other risk factors for osteoporosis, but there is no question that PPIs may facilitate development of osteoporosis in the population at risk. The mechanisms of the association have not been clarified and may involve blockage of the osteoclast PPIs; decreased absorption of calcium as a result of decreased gastric acidity; and increased circulating levels of gastrin, which may stimulate the chronic production of PTH. Frailty is a geriatric syndrome implying increased vulnerability to even minimal stress.[30] The diagnosis of frailty is based on the presence of at least three of five criteria that define the frail phenotype: involuntary weight loss of 10 lbs or more in 6 months, decreased grip strength, decreased gait velocity, decreased energy levels, and difficulty in initiating activities. Although the prevalence of frailty among older cancer patients is not known, it is a fair estimate that frailty is common, especially in patients with metastatic disease who are receiving cytotoxic treatment. The association of frailty and osteoporosis in men was recently described in a prospective assessment of the Osteoporotic Fractures in Men Study (MrOS)[31] and was attributed to low circulating free levels of testosterone in these individuals.

Last, but not least, one should remember that lack of exercise may worsen bone loss, whereas aerobic, weight-bearing, and resistance exercises are effective in promoting bone density, according to several meta-analyses of randomized controlled studies.[32] This finding is particularly relevant to cancer patients, for whom lack of adequate exercise is endemic owing to fatigue, malaise, and complications of treatment.

Prevention and Management of Osteoporosis

Clearly, lifestyle modifications, including smoking cessation, reduced alcohol intake, regular exercise, and adequate nutrition, have an important role in preventing osteoporosis. In randomized controlled studies, exercise seem to reverse bone loss as well.[32]

The focus of this article is on pharmacological interventions that are most easily available to cancer patients. In this section, the following questions will be addressed: Which medications have proven effective in reducing the risk of osteoporotic fractures? What is the risk-benefit of these medications? Which patients should be treated?

TABLE 2

Medications Studied for Prevention of Osteoporotic Fractures

Efficacy and Effectiveness of Available Compounds
Medications assessed in randomized controlled studies are listed in Table 2.[3,18,33] Two types of studies are identified: those aimed at preventing bone fractures in patients with pre-existing osteopenia and osteoporosis, and those aimed at preventing bone loss in patients at risk of developing osteoporosis, such as postmenopausal patients and patients receiving forms of treatment favoring the development of osteoporosis. These include corticosteroids, castration for prostate cancer, and aromatase inhibitors for breast cancer. According to a recent systematic review of osteoporosis treatment,[18] bisphosphonates have been consistently reported to decrease the risk of both vertebral and nonvertebral fractures, including hip fractures. Both oral and intravenous forms are acceptable, and of these, zoledronic acid (Zometa) is probably the most convenient, as it can be administered once yearly.[34] Evidence that estrogen prevents bone fractures is more complex. Three meta-analyses[18] showed a reduction in vertebral and nonvertebral fractures with estrogen treatment, but only in the largest of these studies was the difference vs placebo statistically significant. In the Women's Health Initiative study estrogen reduced the incidence of both vertebral and hip fractures.[18] A difficulty in interpreting the studies related to estrogen is the fact that patients were not randomized to treatment vs no treatment based on their risk of fractures. The only SERM studied in the prevention of osteoporotic fracture, raloxifene (Evista), proved effective in this context. The PTH analog teriparatid and calcitonin both reduced the risk of vertebral and nonvertebral fracture in patients with bone loss.[18] It has been recommended that PTH not be administered for longer than 2 years, because prolonged administration of this agent has been associated with increased risk of osteosarcoma in experimental models. No randomized controlled study showed that the administration of calcium resulted in decreased risk of fractures, but these studies were marred by poor treatment adherence. In the only study in which this parameter was considered, women with good adherence had a significantly reduced risk of fractures in a preplanned analysis.[18]

The evidence for vitamin D and its analogs is complex.[18] No effect was detectable for standard doses of vitamin D, while the analogs proved effective in the majority of studies. High doses of 25-hydroxyvitamin D, such as 700–800 IU daily, also seem to be effective.

The RANK (receptor activator for nuclear factor κ-B) ligand inhibitor denosumab (Prolia), a monoclonal antibody administered subcutaneously every 6 months, proved effective in decreasing the risk of vertebral and hip fractures in patients with osteoporosis.[3,34] The advantages of this compound include its convenient dosing and low toxicity. It is important to emphasize that at present there is no clear evidence that one form of osteoporosis treatment is superior to another. The treatment decision should be based on convenience, toxicity, and cost. In terms of convenience, zoledronic acid, which requires only once-yearly intravenous administration, and denosumab, which requires two injections per year, appear superior to other alternatives. Given the risk of complications, treatment with estrogen alone is not recommended for management of osteoporosis. Women taking hormone-replacement therapy to prevent symptoms of menopause may benefit from this treatment, however, by a reduction in osteoporosis risk. In patients with renal insufficiency, the doses of bisphosphonates should be adjusted.

In regard to concerns about patients at risk who do not have evidence of osteoporosis, the following data should be highlighted:

• Raloxifene and ibandronate (Boniva) prevented bone loss in postmenopausal women.[18]

• Bisphosphonates decreased the risk of vertebral, but not nonvertebral, fractures in patients treated with corticosteroids, whereas the evidence for calcitonin is less clear.[18] No data are available as to the effectiveness of these compounds to prevent bone loss, although this may be inferred from the reduction of fractures. In a recent meta-analysis,[25] vitamin D analogs alfacalcidol and calcitriol were effective in preventing bone loss in patients taking corticosteroids, and they prevented vertebral fractures in those with pre-existing osteoporosis. When compared with bisphosphonates, however, these were consistently less effective in preventing bone loss.[35-37]

• A number of agents, including bisphosphonates and denosumab, prevent bone loss induced by castration in prostate cancer and by aromatase inhibitors in breast cancer.[38-43] None of these studies has yet demonstrated a decreased risk of bone fractures. In breast cancer treated with an aromatase inhibitor, treatment with zoledronic acid was more effective when initiated immediately instead of delaying it for 1 year.[38]

Treatment complications. In general, the treatments to protect against bone loss have been well tolerated, at least over the short term. Complications have included[18]:

• Reflux esophagitis for oral bisphosphonates. Recently some concern was expressed that this complication may increase the risk of esophageal adenocarcinoma;

• Increased risk of osteonecrosis of the jaw, reported both for bisphosphonates and denosumab;

• Renal insufficiency, reported in patients taking zoledronic acid;

• Deep vein thrombosis in patients receiving estrogens or SERMs; and

• Increased incidence of breast cancer, reported in women taking a combination of estrogen and progestin.

Timing of treatment. As already mentioned, some general lifetime precautions may help to prevent or delay bone loss both in women and men. These include smoking cessation, reduced alcohol intake, regular exercise, and a diet rich in calcium. Dietary supplementation with vitamin D is also advisable at a time when hypovitaminosis D may become endemic as a result of inadequate sun exposure. It is important to remember that the accumulation of bone during the early years of life is the best defense against osteoporosis and bone fractures in the later years. A new issue that deserves some attention is polypharmacy, as some common drugs, including PPIs, may increase the risk of bone loss.[29] There is also general agreement that women undergoing menopause should start receiving calcium and vitamin D supplementation. Further, women and men with osteopenia and osteoporosis should receive the treatment judged most appropriate based on convenience, cost, and toxicity. What is less clear is:

• Which patients should be screened for osteopenia and osteoporosis, besides women 65 years of age and older? This question is particularly relevant for cancer patients who receive antineoplastic treatment that is associated with an increased risk of osteoporosis.

• When should treatment be initiated? Should we provide some form of treatment to all individuals at increased risk? In the cancer arena, zoledronic acid and denosumab decrease the rate of bone loss in breast cancer patients treated with aromatase inhibitors and in prostate cancer patients treated with castration, but there is no proof as yet that this translates into decreased risk of bone fracture. This demonstration may be necessary before blank recommendations may be made.{C}

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 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[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 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.

References:

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