Skeletal Efficacy with Parathyroid Hormone in Rats Was Not Entirely Beneficial with Long-Term Treatment

Abstract

We report the consequences of prolonged treatment with recombinant human parathyroid hormone (1-34) (PTH) in male and ovariectomized female rats with mature skeletons. Intact male and osteopenic, ovariectomized, female F-344 rats were evaluated after 1 year of treatment with 0, 8, or 40 g/kg/day s.c. PTH. Males and females were about 6 months of age at study initiation; females were ovariectomized (Ovx) for 5 weeks before initiation of PTH treatment. PTH did not affect the survival of either intact males or ovariectomized females. Qualitative histopathology showed expected changes associated with aging in kidneys and proximal tibiae, with no treatment-related anomalies after 1 year of PTH administration. PTH slightly increased the femoral length of ovariectomized females but not that of males. No significant differences in femoral length were observed between sham and Ovx controls. Proximal femora of the males and ovariectomized females given the high dose of 40 g/kg showed 211 and 186% greater trabecular bone area, 118 and 94% greater cortical thickness, 170 and 189% greater trabecular number, and 321 and 404% greater connectivity (node-to-node struts) compared with respective vehicle controls. Increased trabecular and endocortical surface apposition coincided with a 78 and 70% loss of marrow space for males and females treated with PTH, respectively. Biomechanical strength (ultimate load) of the femoral neck increased by 73 and 76%, respectively, in males and ovariectomized females. Cortical bone analyses of the femoral midshaft showed 105 and 72% increases in bone mineral content, 67 and 55% increases in bone mineral density, and 22 and 10% increases in crosssectional area for males and ovariectomized females, respectively, with altered shape of femora. Biomechanical analyses of the midshaft showed substantial increases in strength and stiffness but a reduction in ultimate strain, which was likely due to the altered geometry of the midshaft for PTH groups. Aging effects on strength of vertebra and femoral midshaft were reversed by PTH treatment. In summary, the 1-year treatment duration, which represents about 50% of lifetime, did not affect survival and was not associated with any treatment-related anomalies in the kidney or skeleton. PTH reversed the aging process in bones but not kidneys and substantially increased bone mass and strength to well beyond normally attained levels. However, compared with short-term studies reported previously, there seemed to be no advantages to extending PTH treatment to 12 months in rat bones.Once daily, subcutaneous administration of human PTH (1-34) stimulates new bone formation in rats, monkeys, and humans (Gasser and Jerome, 1992;Dempster et al

Effects of h-PTH on cancellous bone mass, connectivity, and bone strength in ovariectomized rats with and without sciatic-neurectomy

“…However, recent studies have reported that longer treatment with this growth factor may not be practical, because it is a nonspecific mitogen with a potential for adverse side effects [17]. Furthermore, Sato et al reported that there seemed to be no advantages to extending PTH treatment to 12 months in rat bones compared with short-term treatments [26]. We believed that the regimen of lowdose PTH treatment in this study would be more suitable for clinical usage.…”

Successful treatment of vitamin D unresponsive hypoparathyroidism with multipulse subcutaneous infusion of teriparatide

“…Administration of PTH to animal models has been linked to the development of certain tumors as osteosarcoma (18). A more physiological administration such as the one we used, as the number of pulses delivered per hour in our patient is about the same of normal parathyroid glands (10,11), would probably be safer in this respect; moreover, the total dose given per day in our patient is similar to the one given in the study published by Winer, in which the patients were followed over 3 years without safety problems.…”

Effects of OnceVersusTwice-Daily Parathyroid Hormone 1–34 Therapy in Children with Hypoparathyroidism

“…Animal toxicity studies have raised concerns regarding dose-dependent PTH effects on the bone. Long-term, supraphysiological doses of recombinant human PTH 1-34 (rhPTH), given to rats with normal functioning parathyroid glands, led to osteosarcomas in some experimental animals (19,20). This resulted in a warning against the use of PTH 1-34 in children.…”