Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Abstract

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...

Novel insights into the complex architecture of osteoporosis molecular genetics

“…PTH induces tumorigenesis through upregulation of periostin, which plays a complex role in tumorigenesis . Therefore, safety concerns with abaloparatide are similar to those for teriparatide because they have a similar mechanism of action through the PTHrP1 . Unfortunately, so far, there is no single safe medication for osteoporosis, as all of the available drugs have serious adverse effects and some of them are a potential danger to life .…”

Side effects of drugs for osteoporosis and metastatic bone disease

“…Abaloparatide recently emerged as an osteoanabolic therapy . Therefore, information on adverse effects of abaloparatide is derived from clinical trials with participants followed for up to 43 months.…”

Autocrine and Paracrine Regulation of the Murine Skeleton by Osteocyte-Derived Parathyroid Hormone-Related Protein

“…Like PTH, abaloparatide both acts through the PTHR1 (16) and prevents fractures in osteoporosis. (17,18) Abaloparatide was approved recently by the US Food and Drug Administration (FDA) as TYMLOS TM .…”

“…This action has recently been exploited further by a second clinical agent (abaloparatide), which has high homology to the PTHrP N‐terminal sequence. Like PTH, abaloparatide both acts through the PTHR1 and prevents fractures in osteoporosis . Abaloparatide was approved recently by the US Food and Drug Administration (FDA) as TYMLOS™.…”