Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure

Jean Jacques Body, Allan Lipton, Julie Gralow, Guenther G. Steger, Guozhi Gao, Howard Yeh, Karim Fizazi

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n=255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n=111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every 4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75% (IV BP-naive) and 80% (prior IV BP) after denosumab treatment and 71% (IV BP-naive) and 56% (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73%, IV BP 11%). SRE incidence was low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8%) than the IV BP group (17%). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers independently of prior BP treatment, even in patients who appear to respond poorly to BPs.

Original languageEnglish (US)
Pages (from-to)440-446
Number of pages7
JournalJournal of Bone and Mineral Research
Volume25
Issue number3
DOIs
StatePublished - Jan 1 2010

Fingerprint

Diphosphonates
Neoplasm Metastasis
Bone and Bones
Bone Resorption
Osteoclasts
Denosumab
Spontaneous Fractures
Spinal Cord Compression
Bone Remodeling
Hypercalcemia
Therapeutics
Radiotherapy
Monoclonal Antibodies
Pain
Incidence

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Body, Jean Jacques ; Lipton, Allan ; Gralow, Julie ; Steger, Guenther G. ; Gao, Guozhi ; Yeh, Howard ; Fizazi, Karim. / Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. In: Journal of Bone and Mineral Research. 2010 ; Vol. 25, No. 3. pp. 440-446.
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abstract = "Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n=255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n=111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every 4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75{\%} (IV BP-naive) and 80{\%} (prior IV BP) after denosumab treatment and 71{\%} (IV BP-naive) and 56{\%} (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73{\%}, IV BP 11{\%}). SRE incidence was low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8{\%}) than the IV BP group (17{\%}). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers independently of prior BP treatment, even in patients who appear to respond poorly to BPs.",
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Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. / Body, Jean Jacques; Lipton, Allan; Gralow, Julie; Steger, Guenther G.; Gao, Guozhi; Yeh, Howard; Fizazi, Karim.

In: Journal of Bone and Mineral Research, Vol. 25, No. 3, 01.01.2010, p. 440-446.

Research output: Contribution to journalArticle

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AU - Body, Jean Jacques

AU - Lipton, Allan

AU - Gralow, Julie

AU - Steger, Guenther G.

AU - Gao, Guozhi

AU - Yeh, Howard

AU - Fizazi, Karim

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