Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis

Miller, Paul D.; Hattersley, Gary; Riis, Bente Juel; Williams, Gregory C.; Lau, Eyy; Russo, Luís Augusto Tavares; Alexandersen, Peter; Zerbini, Cristiano A. F.; Hu, Ming‐yi; Harris, Alan G.; Fitzpatrick, Lorraine A.; Cosman, Felicia; Christiansen, Claus

doi:10.1001/jama.2016.11136

Cited by 709 publications

(690 citation statements)

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“…Data reported by Miller and colleagues (1) and in the related article in this issue of JBMR (2) identify abaloparatide as an effective approach to fracture risk reduction. The study by Miller and colleagues…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

“…The same argument has been applied to abaloparatide, (1,2) which behaves like PTHrP(1-36) in the study of initial interaction with receptor.…”

Section: Receptor Interaction and Clearance Of Abaloparatidementioning

confidence: 99%

“…(18,45) Whether PTHrP(1-36) and teriparatide produce a similar anabolic effect but PTHrP(1-36) produces less bone resorption than teriparatide was not evaluated; no histomorphometry was performed. However, a recent large study of iliac crest biopsies from the Miller and colleagues study (1) reported no differences in static or dynamic indices of bone formation or resorption between the two drugs. (46) The possibility that PTHrP(1-36) is anabolic while sparing of resorption would be intriguing but difficult to explain given resorption is an inescapable first phase of bone remodeling.…”

mentioning

confidence: 92%

“…PTH(1-34) (teriparatide) reduces vertebral and nonvertebral fracture risk, in part, by increasing bone matrix volume. Abaloparatide has also recently been reported to reduce morphometric vertebral fracture risk (1,2) and is thus a most welcome addition to the therapeutics of bone fragility. Abaloparatide is claimed to produce its anabolic effect with a much lesser effect on bone resorption than occurs with teriparatide.…”

mentioning

confidence: 99%

“…One possible explanation for a resorption-sparing anabolic effect might be that the higher dose requirement is due to a difference in pharmacokinetics, with PTHrP(1-36) being degraded more rapidly after injection and thus not so widely distributed to activate BMUs. However, if less agonist is available to the receptor, then this should lead to less anabolic and resorptive effects.Data reported by Miller and colleagues (1) and in the related article in this issue of JBMR (2) identify abaloparatide as an effective approach to fracture risk reduction. The study by Miller and colleagues…”

mentioning

confidence: 99%

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Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Martın

Seeman

2016

Journal of Bone and Mineral Research

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L ongevity is increasing the burden of fractures. Although antiresorptive therapy slows remodeling, it does not prevent or repair microstructural deterioration. The challenge is to reconstruct the skeleton. The more advanced the patient's age, the more likely that microstructural deterioration is severe and so the more rational the choice of an anabolic agent as first-line therapy. PTH(1-34) (teriparatide) reduces vertebral and nonvertebral fracture risk, in part, by increasing bone matrix volume. Abaloparatide has also recently been reported to reduce morphometric vertebral fracture risk (1,2) and is thus a most welcome addition to the therapeutics of bone fragility. Abaloparatide is claimed to produce its anabolic effect with a much lesser effect on bone resorption than occurs with teriparatide. In this Commentary, we query the latter proposition, which we suggest contains two misconceptions: first, that with teriparatide treatment an anabolic window exists during which bone formation predominates but then is offset by bone resorption, which follows later, and second that less bone resorption occurs with abaloparatide, leaving the "window" open longer and allowing more bone formation. Anabolic Therapy With Parathyroid Hormone (PTH) and AbaloparatideTo understand the fallacies in these two notions, the mythical anabolic window and the purported lesser resorptive effect of abaloparatide, it is necessary first to discuss the mechanisms of action of PTH. The idea that intermittent injection of PTH might promote bone formation was proposed more than 80 years ago by Albright (3) and shown in rats by Selye.Progress was slow, with no attempt to study PTH treatment clinically until the 1970s. The first clinical trial was published in 2001 (5) and was stopped after 18 months because of a toxicity study that showed dose-dependent development of osteosarcoma in rats treated throughout their lives. (6) With the total number of subjects in the clinical trial reduced to 1600 and the duration of treatment being only 18 months, no potential antihip fracture efficacy could be demonstrated, but vertebral and nonvertebral fracture risk was reduced and bone mineral density (BMD) increased.The efficacy of teriparatide as an anabolic therapy depends on intermittent injections, each achieving a sharp peak of PTH in the blood.(7) When teriparatide therapy is begun, circulating bone formation markers increase rapidly, with a delayed appearance of resorption markers, giving rise to the concept of the "anabolic window." (8,9) This was based on the idea that the initial period of increased anabolic markers reflects an early period of bone formation relatively "unopposed" by resorption but then superseded by subsequent increases in bone resorption. This theory was not based on histomorphometric evidence of changing volumes of bone formation and resorption but rather inferred from finding an early increase in bone "formation" markers, followed by a later increase in bone "resorption" markers.Abaloparatide is a 34-amino acid peptide acting u...

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Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

“…The same argument has been applied to abaloparatide, (1,2) which behaves like PTHrP(1-36) in the study of initial interaction with receptor.…”

Section: Receptor Interaction and Clearance Of Abaloparatidementioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Martın

Seeman

2016

Journal of Bone and Mineral Research

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Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture

Cappola

Shoback

2016

JAMA

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2017

JAMA

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section but regarding the "Postpartum" row, the At Birth (Cord Blood) concentrations of 51.8 (22.8-118.0) should be 48.5 (20.1-117.3) and Infants 7 Months values of 186.5 (106.3-327.2) should be 193.5 (105.5-354.7).These errors did not affect primary outcomes, interpretation, or conclusions of this study. We regret these errors and any confusion this may have caused readers. We have requested that the article be corrected online and a correction notice 2 accompanies this letter.

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Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis

Cited by 709 publications

References 70 publications

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Osteoporosis Therapy in Postmenopausal Women With High Risk of Fracture

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