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CMAJ: Canadian Medical Association Journal (1)
Calcified Tissue International (1)
Therapeutic Advances in Musculoskeletal Disease (1)
Miller, Paul D. (3)
Brown, Jacques P. (1)
Dobnig, Harald (1)
Glass, Emmett V. (1)
Heathman, Michael (1)
Kendler, David L. (1)
Khan, Aliya A. (1)
Lentle, Brian C. (1)
Leslie, William D. (1)
Lewiecki, E. Michael (1)
Marín, Fernando (1)
Nicholson, R. Lawrence (1)
Olszynski, Wojciech P. (1)
Satterwhite, Julie (1)
Watts, Nelson B. (1)
Year of Publication
A review of the efficacy and safety of denosumab in postmenopausal women with osteoporosis
Therapeutic Advances in Musculoskeletal Disease
Denosumab, a fully human monoclonal antibody to RANK ligand [RANK-L]) was approved for the treatment of postmenopausal osteoporosis in June 2010, and is highly effective in reducing the risk of vertebral, nonvertebral, and hip fracture risk. The registration of denosumab was the culmination of the discovery and clarification of the internal bone microenvironment regulation of bone remodeling: the osteoblast-produced competitors: RANK-L and osteoprotogerin; and the osteoclast receptor: RANK. When RANK-L is upregulated in the estrogen-deficient state and exceeds the amount of osteoprotogerin, there is an increase in osteoclastogenesis and bone resorption, and this is the major mechanism for bone mass loss and osteoporotic fractures in the postmenopausal state. The subsequent development of the human monoclonal antibody to RANK-L (denosumab) was the first product developed to reduce bone resorption by inhibiting RANK-L binding to RANK. Denosumab does not accumulate in bone, and has a unique pharmacokinetics so that its biological effect at the registered dose of 60 mg by subcutaneous injection every 6 months is no longer effective, at least as measured by an increase in the bone resorption marker collagen-cross-link C-telopeptide and a decline in bone mineral density as measured by dual energy X-ray absorptiometry. This unique pharmacokinetic profile thus suggests that in order to maintain the effectiveness of denosumab, continuous administration might be necessary. Extension of the registration trial (‘FREEDOM’) 5-year data indicates continued safety and efficacy, and will be extended to 10 years so that even longer-term data will be forthcoming. The profound but reversible suppression of bone turnover that is seen with denosumab partly explains the continuous increase in bone mineral density seen through 8 years of the phase II clinical trials. Denosumab offers a highly effective and safe parenteral therapy for osteoporosis and is being studied long term with the extension of the FREEDOM trial, and in other osteoporotic states – in men and glucocorticoid-induced osteoporosis.
osteoporosis; denosumab; anti-rank ligand; antibody; bone remodeling; bone turnover; bone mineral density; bone turnover; markers; osteoporotic fractures; C-telopeptide
Pharmacokinetics of Teriparatide (rhPTH[1–34]) and Calcium Pharmacodynamics in Postmenopausal Women with Osteoporosis
Glass, Emmett V.
Calcified Tissue International
Teriparatide (rhPTH[1–34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial. Postmenopausal women with osteoporosis received daily subcutaneous injections of either teriparatide 20 μg (4.86 μmol) or placebo, median 21 months’ treatment. Serum teriparatide and calcium concentrations were measured throughout the study. An indirect-response model was developed to describe the pharmacokinetic–pharmacodynamic relationship between teriparatide concentrations and serum calcium response. The pharmacokinetics of teriparatide were characterized by rapid absorption (maximum concentration achieved within 30 min) and rapid elimination (half-life of 1 h), resulting in a total duration of exposure to the peptide of approximately 4 h. Teriparatide transiently increased serum calcium, with the maximum effect observed at approximately 4.25 h (median increase 0.4 mg/dl [0.1 mmol/l]). Calcium concentrations returned to predose levels by 16–24 h after each dose. Persistent hypercalcemia was not observed; one teriparatide 20 μg-treated patient had a predose serum calcium value above the normal range but <11.0 mg/dl (2.75 mmol/l). Following once-daily subcutaneous administration, teriparatide produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The excursion in serum calcium is brief, due to the short length of time that teriparatide concentrations are elevated.
Anabolic agent; Osteoporosis therapy; Peptide hormone; Parathyroid hormone; Teriparatide pharmacokinetics; Calcium pharmacodynamics
The 2002 Canadian bone densitometry recommendations: take-home messages
Khan, Aliya A.
Brown, Jacques P.
Kendler, David L.
Leslie, William D.
Lentle, Brian C.
Lewiecki, E. Michael
Nicholson, R. Lawrence
Olszynski, Wojciech P.
Watts, Nelson B.
CMAJ: Canadian Medical Association Journal
Results 1-3 (3)
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