Effects of Abaloparatide, a Human Parathyroid Hormone-Related Peptide Analog, on Bone Mineral Density in Postmenopausal Women with Osteoporosis

Leder, Benjamin Z.; O’Dea, Louis; Zanchetta, José R.; Kumar, Prasana; Banks, Kate; McKay, Kathleen E.; Lyttle, C. Richard; Hattersley, Gary

doi:10.1210/jc.2014-3718

Cited by 213 publications

(199 citation statements)

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“…In addition, the use of differences in "resorption" and "formation" markers to estimate the change in femoral neck BMD in a 24-week clinical study (10) or total body bone mineral content (BMC) in the rat study (48) takes no account of the many mechanisms that contribute to a rise in BMD. Indeed, BMD often decreases during teriparatide therapy as bone matrix volume increases, in part, because of an increase in porosity and the replacement of older, more mineralized bone with a larger volume of younger, initially less mineralized bone matrix.…”

Section: There Is No Anabolic Window To Open or Closementioning

confidence: 99%

“…(1,2) It is claimed to act with a lesser effect on resorption markers than that with teriparatide. (1,2,10) The first 21 residues are identical with parathyroid hormone-related protein (PTHrP), and the remainder contain a number of substitutions that were planned to improve stability. (11,12) These structural features of abaloparatide have led to it being called a PTHrP analog that is a selective activator of the PTHR1.…”

Section: Anabolic Therapy With Parathyroid Hormone (Pth) and Abaloparmentioning

confidence: 99%

“…(11,12) These structural features of abaloparatide have led to it being called a PTHrP analog that is a selective activator of the PTHR1. (10)(11)(12) Abaloparatide and teriparatide have now been reported to have comparable antivertebral fracture efficacy with a possible earlier and greater effect of abaloparatide in reducing major osteoporotic fractures, an effect suggested to be the result a greater net bone formation due to a lesser effect on bone resorption than teriparatide. (1,2,10) The anabolic effect of teriparatide is predominantly remodeling based in human subjects.…”

Section: Anabolic Therapy With Parathyroid Hormone (Pth) and Abaloparmentioning

confidence: 99%

“…(10)(11)(12) Abaloparatide and teriparatide have now been reported to have comparable antivertebral fracture efficacy with a possible earlier and greater effect of abaloparatide in reducing major osteoporotic fractures, an effect suggested to be the result a greater net bone formation due to a lesser effect on bone resorption than teriparatide. (1,2,10) The anabolic effect of teriparatide is predominantly remodeling based in human subjects. (13,14) The delay in resorption marker increase after starting PTH treatment can be explained by the principles of basic multicellular unit (BMU)-based remodeling.…”

Section: Anabolic Therapy With Parathyroid Hormone (Pth) and Abaloparmentioning

confidence: 99%

“…Moreover, differences in concentration of the markers in a blood sample are determined more by differences in remodeling rate and so the surface extent of remodeling rather than differences in BMU balance. Neither of the surface extents of resorption and formation inform as to whether there is net removal of, or deposition upon, the periosteal, intracortical, endocortical, or trabecular surfaces.In addition, the use of differences in "resorption" and "formation" markers to estimate the change in femoral neck BMD in a 24-week clinical study (10) or total body bone mineral content (BMC) in the rat study (48) takes no account of the many mechanisms that contribute to a rise in BMD. Indeed, BMD often decreases during teriparatide therapy as bone matrix volume increases, in part, because of an increase in porosity and the replacement of older, more mineralized bone with a larger volume of younger, initially less mineralized bone matrix.…”

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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: There Is No Anabolic Window To Open or Closementioning

confidence: 99%