Dose—Response Effects of Intermittent PTH on Cancellous Bone in Hindlimb Unloaded Rats

Abstract

HLU suppressed bone formation and resulted in bone loss in the tibial metaphysis of 6-monthold male rats. A human therapeutic dose of intermittent PTH (1 µg/kg/day) prevented the skeletal changes associated with HLU.Introduction: Skeletal unloading of skeletally mature rats results in trabecular thinning in the proximal tibial metaphysis, which is in part caused by a decrease in bone formation. We examined the efficacy of PTH in preventing the detrimental skeletal effects that occur with hindlimb unloading (HLU). Materials and Methods: Six-month-old male Fisher 344 rats were HLU and treated with vehicle or recombinant human PTH(1-34) at 1, 5, 20, or 80 g/kg/day for 2 weeks. The bone response was measured by CT analysis of bone structure, histomorphometric analysis of static and dynamic bone parameters, and Northern blot analysis of mRNA levels for bone matrix proteins. The PTH-treated HLU animals were compared with vehicle-treated HLU and pair-fed normal weight-bearing controls. Results: Unloading resulted in a decrease in cancellous bone volume that was caused in part by a dramatic 83% decrease in bone formation. All dose rates (1-80 g/kg/day) of human PTH(1-34) significantly increased bone formation rates compared with vehicle-treated HLU controls. There was a dose response, and the highest dose rate of the hormone increased bone formation compared with normal weight-bearing rats by 708% (p < 0.0001). The increases in bone formation were accompanied by increases in mRNA levels for type 1 collagen, osteocalcin, and osteonectin. Also, treatment with PTH resulted in increases in mineral apposition rate and double-labeled perimeter, but the latter was disproportionally increased at high dose rates. A therapeutic dose of PTH (1 g/kg/day) prevented disuse-induced trabecular thinning, whereas high-dose PTH (80 g/kg/day) increased trabecular thickness compared with normal weight-bearing rats. Conclusions: These findings reveal that administration of a therapeutic dose of PTH to HLU rats prevents the decrease in bone formation and trabecular thinning, whereas high dose rates of the hormone increase bone formation and trabecular thickness to values that exceed normal values.

Intermittent parathyroid hormone (PTH) treatment and age‐dependent effects on rat cancellous bone and mineral metabolism

“…cDNA probes were labeled with 32 P by random sequence hexanucleotide primer extension using the Megaprime DNA labeling kit (Amersham, Arlington Heights, IL) up to an activity of minimum 6 Â 10 6 cpm/ml for collagen I (Coll I), osteonectin (ON), and osteocalcin (OC), and to 1 Â 10 6 cpm/ml for cDNA-plasmid probe for 18S rRNA, which was used to correct for unequal loading of RNA in the agarose gel. Hybridization was carried out for 80 min at 658C, and the membranes were washed thereafter for 30 min in 3Â SSC at 438C, 15 min in 1Â SSC at 438C, and, if necessary, once again for 15 min in 0.5Â SSC at 558C and 658C, consecutively.…”

Effects of low-dose parathyroid hormone on bone mass, turnover, and ectopic osteoinduction in a rat model for chronic alcohol abuse

“…Thus, low dose PTH treatment in the rat results in site specific increases in bone formation similar to the therapeutic use of the hormone in humans. This finding contrasts with high dose PTH treatment in rats which results in a pronounced bone anabolic response in cortical bone [10,11].…”

“…The section was polished between a roughened ground glass plate and cork and then illuminated with UV light to measure the fluorochrome labels. M.Pm/B.Pm, MAR, and BFR/B.Pm were determined as described [10,11].…”

“…The effects of ongoing alcohol consumption on therapies to treat osteoporosis or accelerate bone healing are uninvestigated in humans and only a small number of studies have been performed in animal models [10,11]. Animal studies to date suggest a detrimental effect of alcohol on the skeletal response to PTH.…”

“…However, only very high dose rates of the hormone have been modeled. Recent dose response studies suggest that high doses of PTH impair the ability to detect and model "life style" factors that influence the skeletal response to PTH in humans [10,11]. Additional studies that better model the human therapeutic application of PTH are warranted due to the high prevalence of alcohol consumption in countries with high rates of osteoporosis.…”