Bone loss is quite common in women. Osteoporosis is as common in Singapore as it is in Western countries and the incidence of hip fractures has risen five times among women in the last 30 years. The World Health Organization defines osteoporosis as bone density (t- score) of less than or equal to - 2.5 standard deviation from the peak bone mass of a normal woman. Osteopenia is defined as a bone density (t- score) of less than –1 but more than - 2.5 standard deviation from the peak bone mass.

The increasing availability of bone mineral density (BMD) measurements allows the implementation of effective therapeutic interventions to those at risk for fractures before they occur. Standard treatments for breast cancer such as adjuvant chemotherapy or hormonal therapy can increase bone loss, and may therefore increase the risk of osteoporosis. Peri-menopausal women treated with standard adjuvant chemotherapy often develop early menopause. This ovarian failure is associated with accelerated bone loss. So, although the management of osteopenia and osteoporosis in women with breast cancer usually does not differ from women without breast cancer, women who have received treatment for breast cancer are at a possibly earlier risk for osteoporosis.

Aromatase inhibitors are now more widely used for adjuvant treatment of postmenopausal women with early-stage, estrogen receptor–positive breast cancer in Singapore. With a more profound depletion of estrogen, these ladies may be subjected to greater bone loss.

Current guidelines for the treatment of bone loss

As mentioned, the management of osteopenia and osteoporosis in women with breast cancer usually does not differ from women without breast cancer. This can be divided into non-pharmacologic or pharmacologic treatment strategies. Non-pharmacologic strategies include adequate dietary calcium and vitamin D intake, encouraging weight-bearing exercise, and counseling about the relationship between smoking and alcohol and bone loss.

Aerobics, weight bearing and resistance exercises are all effective in increasing the BMD of the spine in postmenopausal women. Walking is also effective on the hip. In addition to encouraging lifestyle changes, regular BMD monitoring should be performed in women who develop chemotherapy-induced ovarian failure and are at risk for bone loss, or for those who are on aromatase inhibitors.

NON-PHARMACOLOGIC MANAGEMENT OF BONE LOSS
	Stop smoking
	Regular weight-bearing exercise
	Maintain ideal BMI
	Limit alcohol intake
	Limit fat intake
	Eat more fish, chicken, nuts, and legumes
	Eat 5 or more servings of fruit and vegetables/d
	Eat whole grain breads and cereals

Preventing bone loss is the aim of non-pharmacologic interventions. This can be widely recommended for patients with normal bone mass or osteopenia, who have completed adjuvant chemotherapy and or are on Tamoxifen and aromatase inhibitors. It is controversial if patients with osteopenia require active pharmacologic intervention. Active treatment with pharmacologic interventions in osteopenia depends on age and the presence of other risk factors for fractures. It has to be decided on an individual basis.

For osteoporosis, mere non-pharmacologic intervention is not adequate. The decision to intervene with pharmacologic therapy involves clinical judgment based on an overall assessment of a patient and not just BMD measurement. All therapeutic agents currently approved for the prevention and treatment of osteoporosis work through inhibiting bone resorption. Maintaining adequate estrogen levels remains the most important way of maintaining adequate bone density in women. Traditionally women with bone loss can be offered estrogens. However, there are many contraindications to prescribing estrogens in women. The table below shows just some contraindications. Certainly in this article, women we talk about all have either active breast cancer or a history of breast cancer and therefore are absolutely contraindicated to receiving estrogen in any form.

CONTRAINDICATIONS OF ESTROGEN USE IN BONE LOSS
	Absolute contraindications
	History of active breast cancer, or breast cancer in remission Undiagnosed or abnormal and or postmenopausal vaginal bleeding History of or active clot
	Relative contraindications
	History of thromboembolic disease Familial hypertriglyceridemia Uterine leiomyomas Established and treated uterine cancer Strong family history of breast cancer

Additional calcium supplementation in addition to diet can result in a small beneficial effect on bone mass throughout postmenopausal life. Postmenopausal women receiving supplemental calcium over a three-year period in a placebo-controlled, randomized clinical trial had a stable BMD in the lumbar spine and femoral neck when compared to women taking placebo. Dietary calcium is as effective as calcium in tablet form at maintaining calcium levels, and a systematic review suggests that 1000 mg of dietary calcium per day leads to a 24% reduction in hip fractures. Most adults should consume 1,000 mg of elemental calcium per day for optimal bone health. Everyone older than 65 years should ingest 1,500 mg of elemental calcium per day for optimal bone health.

Vitamin D enhances dietary calcium absorption in the gastrointestinal tract, and its subsequent resorption in the kidneys. Unfortunately, its benefits seems to be limited to frail older people confined to institutions, who benefit by sustaining fewer hip and other non-vertebral fractures if given vitamin D with calcium supplements. The effectiveness of vitamin D alone in fracture prevention is unclear. Dose, frequency, and route of administration of vitamin D in older people require further investigation. However, the general guideline is for intake of 400 U to 800 U a day.

Bisphosphonates are effective for preventing most forms of bone loss. All bisphosphonates act similarly on bone in binding permanently to mineralized bone surfaces and inhibiting osteoclastic activity. The Fracture Intervention Trial (FIT) investigated the effect of alendronate on the risk of fractures in postmenopausal women with low bone mass. The risk of clinical fracture in those taking alendronate was one half that of women in the placebo group.

In ladies with breast cancer, bisphosphonates are also specific inhibitors of osteoclasts. The indications for these drugs are the treatment of hypercalcemia of malignancy, in breast cancer patients with established skeletal metastases, and in the prevention and treatment of osteoporosis. Results of several randomized trials demonstrate that that the oral bisphosphonates can lessen BMD loss in women. Bisphosphonates of proven clinical benefit includes alendronate and risedronate.

Some patients cannot tolerate the side effects of oral bisphosphonates, suffering its adverse effects of oesophagitis and gastritis. In these ladies, intravenous bisphosphonates can be considered. Presently available intravenous bisphosphonates include pamidronate, zolendronic acid and ibandronate. Zolendronic acid can be given annually to prevent bone loss. In the treatment of cancer induced bone loss, several studies have been shown to preserve BMD and therefore presumably prevention of osteoporosis. However, whether a prevention of osteoporosis leads to a correlated reduction of fracture risk in this group of patients, still remains to be proven. More studies are underway.

Calcitonin is also an option in the treatment of osteoporosis. However, for reasons that are not clear, some patients can develop resistance to calcitonin, resulting in ensuing continued bone loss despite use of calcitonin.

Raloxifene is a selective estrogen receptor modulator (SERM) studied and proven to prevent osteoporosis. Although Raloxifene is thought to block estrogen in a similar manner to Tamoxifen, it inhibits trabecular and vertebral bone loss by blocking the activity of cytokines, which stimulate bone resorption. However, as a treatment ofr invasive breast cancer, its wide spread use as a replacement of Tamoxifen or in combination with Tamoxifen as adjuvant hormonal therapy, or as a follow on treatment of breast cancer after cessation of Tamoxifen cannot recommended in view of possible detrimental effects of the concurrent or sequential use of two different SERMs. More studies would have to be conducted.

In many patients with uncomplicated osteoporosis, bisphosphonates will be prescribed by their primary treating medical oncologist. However, more complicated situations warrant the multidisciplinary care of a nutritionist, medical oncologist and endocrinologist in these patients.

KEY LEARNING POINTS
Management of bone loss associated with breast cancer patients includes
	Regular monitoring of patients with bone mineral density scans
	For patients at risk of bone loss, institute non-pharmacologic interventions early
	For patients at high risk of osteoporosis (who has not yet developed osteoporosis), or has established osteoporosis, pharmacologic interventions can be recommended
	Patients at high risk of osteoporosis includes post menopausal ladies with breast cancer, patients with pre-mature ovarian failure, and patients on aromatase inhibitors

 

See Hui Ti
Medical Oncology
National Cancer Centre, Singapore