Teriparatide [rhPTH (1-34)], But Not Strontium Ranelate, Demonstrated Bone Anabolic Efficacy in Mature, Osteopenic, Ovariectomized Rats

Li, Yanfei; Zeng, Qing; Porras, Leah L.; Harvey, A. McGehee; Moore, Terry L.; Shelbourn, Timothy L.; Dalsky, G. P.; Wronski, Thomas J.; Aguirre, J. Ignacio; Bryant, Henry U.; Sato, Masahiko

doi:10.1210/en.2010-1112

Cited by 36 publications

(29 citation statements)

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“…This has been assessed using both biochemical markers and histomorphometry and implies that the induced formation is taking place predominantly on quiescent surfaces. (49)(50)(51)(52)(53)(54)(55)(56)(57) The same outcome is reported by Varela and colleagues, (48) where aged osteopenic rats were treated with three doses of abaloparatide (1, 5, and 25 mg/kg), resulting in substantial doseresponsive increases in BMD and bone formation, assessed by histomorphometry, without any significant increase in resorption parameters. It is interesting that such low doses of abaloparatide were used in this study, given the choice in the clinical trial of a dose 4 times higher than that of teriparatide, and the known very much higher dose of PTHrP(1-36) required in mice and in human subjects.…”

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confidence: 68%

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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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“…(50) In these latter two studies and many other studies in aged ovariectomized (OVX) rats, some using low PTH doses, others using relatively high doses (100 mg/kg),…”

Section: Abaloparatide Is An Anabolic Agent But Is It Relatively Resmentioning

confidence: 99%

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Martın

Seeman

2016

Journal of Bone and Mineral Research

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“…Scans of the femora were taken at 0.4 and 4.4 mm from the end of the growth plate for distal metaphysis and midshaft analyses, respectively. Bone mineral content (BMC) and bone area were reported using Aloka software (SYS-C320 version 1.5) as previously described [29]. Bone mineral density (BMD) was calculated as BMC normalized to bone volumetric area [29].…”

Section: Methodsmentioning

confidence: 99%

“…Bone mineral content (BMC) and bone area were reported using Aloka software (SYS-C320 version 1.5) as previously described [29]. Bone mineral density (BMD) was calculated as BMC normalized to bone volumetric area [29]. μCT measurements of left hemi-mandibles were conducted at Charles River Laboratories Montreal (Senneville, Québec, Canada), with a Scanco μCT 100 scanner (Scanco Medical AG, Brüttisellen, Switzerland) with a dose of 70 kVp, 114 μA, 8 W and at a isotropic voxel resolution of 5 μm.…”

Section: Methodsmentioning

confidence: 99%

Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice

et al. 2017

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There has been growing recognition of the essential roles of citrate in biomechanical properties of mineralized tissues, including teeth and bone. However, the sources of citrate in these tissues have not been well defined, and the contribution of citrate to the regulation of odontogenesis and osteogenesis has not been examined. Here, tooth and bone phenotypes were examined in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient C57BL/6 mice at 13 and 32 weeks of age. Slc13a5 deficiency led to defective tooth development, characterized by absence of mature enamel, formation of aberrant enamel matrix, and dysplasia and hyperplasia of the enamel organ epithelium that progressed with age. These abnormalities were associated with fragile teeth with a possible predisposition to tooth abscesses. The lack of mature enamel was consistent with amelogenesis imperfecta. Furthermore, Slc13a5 deficiency led to decreased bone mineral density and impaired bone formation in 13-week-old mice but not in older mice. The findings revealed the potentially important role of citrate and Slc13a5 in the development and function of teeth and bone.

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“…Lumbar vertebra were excised at necropsy and analysed by quantitative CT (Stratec) and then prepared for biomechanical testing. Strength was evaluated by loading excised vertebra to failure (Ma et al, 2011). Serum calcium was measured at the end of the 8 week study period for all rats.…”

Section: Animal Studiesmentioning

confidence: 99%

Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism

Krishnan

Chen

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEHuman parathyroid hormone (PTH) is critical for maintaining physiological calcium homeostasis and plays an important role in the formation and maintenance of the bone. Full-length PTH and a truncated peptide form are approved for treatment of hypoparathyroidism and osteoporosis respectively. Our initial goal was to develop an improved PTH therapy for osteoporosis, but clinical development was halted. The novel compound was then repurposed as an improved therapy for hypoparathyroidism. EXPERIMENTAL APPROACHA longer-acting form of PTH was synthesised by altering the peptide to increase cell surface residence time of the bound ligand to its receptor. In vitro screening identified a compound, which was tested in an animal model of osteoporosis before entering human trials. This compound was subsequently tested in two independent animal models of hypoparathyroidism. KEY RESULTSThe peptide identified, LY627-2K, exhibited delayed internalization kinetics. In an ovariectomy-induced bone loss rat model, LY627-2K demonstrated improved vertebral bone mineral density and biomechanical properties at skeletal sites and a modest increase in serum calcium. In a Phase I clinical study, dose-dependent increases in serum calcium were reproduced. These observations prompted us to explore a second indication, hypoparathyroidism. In animal models of this disease, LY627-2K restored serum calcium, comparing favourably to treatment with wild-type PTH. CONCLUSIONS AND IMPLICATIONSWe summarize the repositioning of a therapeutic candidate with substantial preclinical and clinical data. Our results support its repurposing and continued development, from a common indication (osteoporosis) to a rare disease (hypoparathyroidism) by exploiting a shared molecular target.

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Teriparatide [rhPTH (1-34)], But Not Strontium Ranelate, Demonstrated Bone Anabolic Efficacy in Mature, Osteopenic, Ovariectomized Rats

Cited by 36 publications

References 57 publications

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

Defective enamel and bone development in sodium-dependent citrate transporter (NaCT) Slc13a5 deficient mice

Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism

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