Frequency of Teriparatide Administration Affects the Histological Pattern of Bone Formation in Young Adult Male Mice

Abstract

Evidence supports that daily and once-weekly administration of teriparatide, human (h)PTH(1-34), enhance bone mass in osteoporotic patients. However, it is uncertain whether different frequencies of hPTH(1-34) administration would induce bone formation similarly in terms of quantity and quality. To investigate that issue, mice were subjected to different frequencies of PTH administration, and their bones were histologically examined. Frequencies of administration were 1 time/2 days, 1 time a day, and 2 and 4 times a day. Mice were allocated to either to control or to 3 different dosing regimens: 80 μg/kg of hPTH(1-34) per injection (80 μg/kg per dose), 80 μg/kg of hPTH(1-34) per day (80 μg/kg · d), or 20 μg/kg of hPTH(1-34) per day (20 μg/kg · d). With the regimens of 80 μg/kg per dose and 80 μg/kg · d, high-frequency hPTH(1-34) administration increased metaphyseal trabecular number. However, 4 doses per day induced the formation of thin trabeculae, whereas the daily PTH regimen resulted in thicker trabeculae. A similar pattern was observed with the lower daily hPTH(1-34) dose (20 μg/kg · d): more frequent PTH administration led to the formation of thin trabeculae, showing a thick preosteoblastic cell layer, several osteoclasts, and scalloped cement lines that indicated accelerated bone remodeling. On the other hand, low-frequency PTH administration induced new bone with mature osteoblasts lying on mildly convex surfaces representative of arrest lines, which suggests minimodeling-based bone formation. Thus, high-frequency PTH administration seems to increase bone mass rapidly by forming thin trabeculae through accelerated bone remodeling. Alternatively, low-frequency PTH administration leads to the formation of thicker trabeculae through bone remodeling and minimodeling.

Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit

“…Without coupling with bone resorption, the rate of bone formation would be slow; this would concomitantly make synchronized and stable bone formation achievable. To support our interpretation, Yamamoto et al, recently reported that in a young adult male mouse model, the low-frequency administration of TPTD led to the formation of thicker trabecular bone through bone mini-modeling and remodeling, while the high-frequency administration of TPTD led to a rapid increase in bone formation by enhanced bone remodeling [12]. …”

“…The high-frequency administration of TPTD was associated with the formation of thin trabeculae and porotic cortices, with a rapid increase in the BMD and accelerated bone remodeling. In contrast, the low-frequency administration of TPTD led to the formation of thicker trabeculae with the maintenance of thick cortices [12]. …”

Osteogenic Factor Runx2 Marks a Subset of Leptin Receptor-Positive Cells that Sit Atop the Bone Marrow Stromal Cell Hierarchy

“…Several studies have demonstrated that intermittent PTH treatment induces remedial action against osteoporosis due to anabolic effects on bone tissue 25–28 . Researchers have found that osteoblast precursors are increased along the bone surfaces in response to PTH treatment 27–30 .…”

Biological application of focus ion beam-scanning electron microscopy (FIB-SEM) to the imaging of cartilaginous fibrils and osteoblastic cytoplasmic processes

“…5 and 6, we could hypothesize that osteoblasts seem to be able to "stock" their cytoplasmic processes on the osteoid in the primary trabeculae, which is marked by a high bone formation rate (17,18). We have previously demonstrated the distribution of osteocytes and their cytoplasmic processes were irregularly-arranged in the immature primary trabeculae, though they were regular in the mature cortical bone (14)(15)(16).…”

“…Since bone formation rate is extremely high in primary trabeculae (16)(17)(18), one may wonder whether an osteoblast can produce new cytoplasmic processes at the same rate that it forms new bone. Alternatively, is it possible that cytoplasmic processes are synthesized in advance and "stocked" beneath the osteoblasts until needed?…”