Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab

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Abstract

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.

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Most cited references 112

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Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

R M Neer, C Arnaud, J. Zanchetta … (2001)

Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

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Sex steroids and the construction and conservation of the adult skeleton.

Sundeep Khosla, L. Joseph Melton, B Riggs (2002)

Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4-8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

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Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results.

Kimberly A. ROEHL, Misop Han, Christian G. Ramos … (2004)

We updated a long-term cancer control outcome in a large anatomical radical retropubic prostatectomy (RRP) series. We also evaluated the perioperative parameters that predict cancer specific outcomes following surgery. From May 1983 to February 2003, 1 surgeon (WJC) performed RRP in 3,478 consecutive men. Patients were followed with semiannual serum prostate specific antigen (PSA) tests and annual digital rectal examinations. We used Kaplan-Meier product limit estimates to calculate actuarial 10-year probabilities of biochemical progression-free survival, cancer specific survival and overall survival. Multivariate Cox proportional hazards models were used to determine independent perioperative predictors of cancer progression. At a mean followup of 65 months (range 0 to 233) actuarial 10-year biochemical progression-free, cancer specific and overall survival probabilities were 68%, 97% and 83%, respectively. On multivariate analysis biochemical progression-free survival probability was significantly associated with preoperative PSA, clinical tumor stage, Gleason sum, pathological stage and treatment era. Cancer specific survival and overall survival rates were also significantly associated with clinicopathological parameters. RRP can be performed with excellent survival outcomes. Favorable clinicopathological parameters and treatment in the PSA era are associated with improved cancer control.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Med Insights Oncol

Journal ID (iso-abbrev): Clin Med Insights Oncol

Journal ID (publisher-id): 101467911

Title: Clinical Medicine Insights. Oncology

Publisher: Libertas Academica

ISSN (Electronic): 1179-5549

Publication date Collection: 2012

Publication date (Electronic): 16 August 2012

Volume: 6

Pages: 287-303

Affiliations

[1 ]College of Medicine, Penn State Hershey Medical Center, Hershey, PA, USA

[2 ]Massachusetts General Hospital Cancer Center, Boston, MA, USA

[3 ]Seattle Cancer Care Alliance, Seattle, WA, USA

[4 ]Amgen Inc. Thousand Oaks, CA, USA

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Corresponding author email: alipton@ 123456psu.edu

Article

Publisher ID: cmo-6-2012-287

DOI: 10.4137/CMO.S8511

PMC ID: 3427033

PubMed ID: 22933844

SO-VID: 64253e36-a499-41e8-93f5-5e2df6051fd2

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This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.

Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab

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Karger: Oncology

Most cited references 112

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

Sex steroids and the construction and conservation of the adult skeleton.

Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results.

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