Denosumab viable therapy for preserving bone health of patients with cancer

Denosumab is a monoclonal antibody inhibitor of receptor activator of nuclear factor kappa B ligand that decreases the activity of osteoclasts.

This decreases bone resorption and increases bone mineral density (BMD).

Denosumab (Xgeva, Prolia; Amgen) at the higher dose of 120 mg subcutaneously every 4 weeks previously has been shown to decrease the rate of skeletal-related events in patients with multiple myeloma, breast cancer, prostate cancer and other solid tumors.

Denosumab in the lower dose of 60 mg subcutaneously every 6 months also is useful in the treatment of osteoporosis in noncancer postmenopausal women. This therapy is well tolerated, but the following adverse effects can be troublesome: fatigue, headache, rash, nausea, diarrhea, myalgias, hypophosphatemia and hypocalcemia.

Osteonecrosis of the jaw is a serious adverse effect seen with IV bisphosphonates and denosumab. The reported incidence varies widely, but in clinical trials, it usually ranges from 1% to 2%, and it usually is seen in roughly the same incidence with IV bisphosphonates and denosumab.

New studies have explored the use of denosumab for other specific indications in the preservation of bone health in patients with cancer.

Cancer treatment-induced bone loss (CTIBL) affects men and women undergoing hormonal therapy for prostate and breast cancer. CTIBL leads to osteoporosis and increases the risk for fracture.

Lisa K. Lohr

In men receiving androgen deprivation therapy (ADT) for prostate cancer, the bone loss is much greater than that seen in the normal aging process. In postmenopausal women receiving an aromatase inhibitor, CTIBL develops due to estrogen deprivation.

The loss of BMD increases with the duration of the aromatase inhibitor and increases the risk for fracture. Although tamoxifen is a partial agonist in bone, premenopausal women receiving tamoxifen therapy can develop CTIBL because its effect is much less than natural estrogens. However, in postmenopausal women, tamoxifen usually increases BMD.

CTIBL can result in dramatic reductions in bone density with an increase of fractures, which can cause significant morbidity in patients with cancer. Interventions such as weight-bearing exercise and calcium/vitamin D supplementation are not adequate to prevent CTIBL.

It has been recommended that all patients being treated with medical castration, aromatase inhibitors or ADT should have BMD monitored at baseline and every 1 to 2 years thereafter. Adequate calcium (1,000 mg to 1,500 mg daily) and vitamin D (800 U daily) intake should be assured, and vitamin D deficiencies should be corrected.

Active treatments for CTIBL until now have been limited to oral and IV bisphosphonates. Denosumab has been studied for use in CTIBL, and the FDA recently approved its use in this indication.

CTIBL in breast cancer

One group of researchers randomly assigned 252 women with non-metastatic breast cancer to receive denosumab 60 mg subcutaneously every 6 months for four doses or placebo.

All patients enrolled had baseline BMD at lumbar spine, total hip or femoral neck with a T-score of –1 to –2.5. All patients were treated with an aromatase inhibitor.

The primary endpoint of this study was the effect on the BMD at the lumbar spine, a surrogate endpoint for fracture.

The results showed a progressive decline of BMD in the placebo group, starting at the first month, and a continued decline through the 24th month when the study ended.

The BMD of the group treated with denosumab started increasing at the first month and continued increasing through the 24th month.

Table 1 shows the differences in BMD between denosumab and placebo in this trial.

Similar results were found in women who received less than 6 months of aromatase inhibitor, as well as in women who had been treated with an aromatase inhibitor for more than 6 months.

The researchers concluded that 2 years of lower-dose denosumab therapy significantly increased BMD in patients with breast cancer receiving aromatase inhibitor therapy.

CTIBL in prostate cancer

Another group of investigators studied denosumab in 1,468 men with non-metastatic prostate cancer receiving ADT, regardless of baseline BMD scores.

These men were randomly assigned to receive either denosumab 60 mg subcutaneously every 6 months for four doses or placebo.

Most patients (63.1%) had a baseline lumbar spine or hip T-score of –1 to –2.5. Most of the patients had received ADT for more than 6 months at study entry.

As in the previous study, the patients in the placebo group had a steady decline in BMD that started in the first month and continued through the 24 months of the study and another 12 months of observation. The men in the denosumab group experienced a steady increase in BMD, starting in the first month and continuing through the 36th month.

Table 2 shows some results from this study.

The researchers of this trial concluded that the 2-year treatment with lower-dose denosumab significantly increased BMD and reduced the risk for fracture in non-metastatic patients with prostate cancer treated with ADT.

The results of these two trials confirm the utility of a 2-year treatment with denosumab 60 mg subcutaneously every 6 months in patients with non-metastatic prostate and breast cancer.

Denosumab now offers an alternative to therapy with oral or IV bisphosphonates for CTIBL in patients with breast and prostate cancer.

Prevention of bone metastases

Another group of investigators recently reported the results of a placebo-controlled trial of denosumab in the prevention of bone metastases or death in men with non-metastatic prostate cancer.

The 1,432 patients were at high risk for bone metastases because of high PSA level, short PSA doubling time or both.

They were randomly assigned to receive denosumab 120 mg subcutaneously every 4 weeks — the dose used in the prevention of skeletal-related events — or placebo. The primary endpoint was the bone metastasis-free survival or death from any cause.

Table 3 shows results from this trial.

The approximate 4-month delay in the onset of bone metastases in these patients with prostate cancer is comparable to the delay in skeletal-related events in patients treated with denosumab.

The researchers concluded that treatment with higher-dose denosumab delays the formation of bone metastases in prostate cancer but does not improve OS in these patients.

Summary

These studies support the use of lower-dose denosumab in CTIBL.

Higher-dose denosumab delays the onset of bone metastases in patients with prostate cancer but does not improve OS.

Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacy specialist and oncology medication therapy management provider at Masonic Cancer Center at the University of Minnesota/Fairview in Minneapolis. She also is a HemOnc Today Editorial Board member. Disclosure: Dr. Lohr reports no relevant financial disclosures.

For more information:

• Ellis GK. J Clin Oncol. 2008;26:4875-4882.
• Smith MR. Lancet. 2011;doi:10.1016/S0140-6736(11)61226-9.
• Smith MR. N Engl J Med. 2009;361:745-755.