Bone tissue and its mineralization in aged estrogen-depleted rats after long-term intermittent treatment with parathyroid hormone (PTH) analog SDZ PTS 893 or human PTH(1-34).
Intermittently administered parathyroid hormone (PTH) is a potent bone anabolic agent. We aimed to determine the impact of long-term treatment with PTH on bone structure, dynamics, and mineralization. We ovariectomized (ovx) 1-year-old rats with the exception of a baseline and a sham-operated group. Twelve weeks later, a 36 week treatment with PTH analog SDZ PTS 893 (12.5, 25, 50, 100 microg/kg), human PTH(1-34) (25, 50, 100 microg/kg), or vehicle (ovx, sham) was initiated. Bone dynamics, structure, and mineralization were evaluated in the lumbar spine and in the femoral diaphysis. Cancellous bone turnover was elevated 12 weeks postovariectomy in estrogen-deficient, vehicle-treated animals, but returned to the level of the sham group by 48 weeks. The animals experienced substantial cancellous bone loss associated with a reduction of trabecular number and presented with a partly rod-like trabecular network. After 36 weeks of treatment with SDZ PTS 893 or human PTH(1-34), cancellous bone formation rates and turnover were raised in all treated groups compared with age-matched controls. The mineral apposition rate was increasing with dose. This amplified matrix synthesis led to trabecular thickening, but not to an increase in trabecular number, resulting in a crude, plate-like cancellous network with a high bone volume fraction. Fluorochrome label-based cortical bone dynamics demonstrated that a thick ring of new bone was formed at the endocortex by activation of modeling drifts during treatment. Treatment-induced cortical bone formation was increased with dose at the subperiosteal and endocortical envelopes, but substantially higher at the latter. Intracortical bone turnover was elevated near the endocortex. Bone mineralization was undisturbed in all compartments. The average degree of mineralization was lowered slightly, reflecting the increased portion of new bone formed during treatment. In summary, the main anabolic effect was mediated for both peptides by an increase in bone apposition with dose, persisting throughout treatment that lasted more than one third of the lifespan of the rats, and direct activation of bone-forming surfaces. As a result, a substantial amount of new bone, maintained at elevated turnover and adequate mineralization levels, formed predominantly at compartments exposed to bone marrow.
Kneissel
M
M
Bone Metabolism Unit, Therapeutic Area of Arthritis and Bone Metabolism, Novartis Pharma AG, Basel, Switzerland. michaela.kneissel@pharma.novartis.com
Boyde
A
A
Gasser
J A
JA
D000375:Aging / Q000502:physiology*; D000818:Animals; D016723:Bone Remodeling; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects*; D002113:Calcification, Physiologic; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019379:Teriparatide / Q000031:analogs & derivatives* / Q000494:pharmacology*
D004967:Estrogens; D010281:Parathyroid Hormone; D010446:Peptide Fragments; C403923:parathyroid hormone (1-34), Leu(8),Asp(10),Lys(11),Ala(16),Gln(18),Thr(33),Ala(34)-; D019379:Teriparatide