Prevention and Management of Osteoporosis
Clearly, lifestyle modifications, including smoking cessation, reduced alcohol(Drug information on 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.
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?
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, 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(Drug information on zoledronic acid) (Zometa) is probably the most convenient, as it can be administered once yearly. Evidence that estrogen prevents bone fractures is more complex. Three meta-analyses 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. 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(Drug information on 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. 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.
The evidence for vitamin D and its analogs is complex. 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.
• Bisphosphonates decreased the risk of vertebral, but not nonvertebral, fractures in patients treated with corticosteroids, whereas the evidence for calcitonin is less clear. 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, vitamin D analogs alfacalcidol(Drug information on alfacalcidol) and calcitriol(Drug information on 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.
Treatment complications. In general, the treatments to protect against bone loss have been well tolerated, at least over the short term. Complications have included:
• 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(Drug information on 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. 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.