ABSTRACT: 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.
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(Drug information on alfacalcidol))[25] and bisphosphonates[26] may ameliorate corticosteroid-induced osteoporosis.
Other factors that may influence bone density include protein-calorie malnutrition, excessive alcohol(Drug information on 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.
