Catabolic and anabolic actions of parathyroid hormone on the skeleton

Abstract

PTH, an 84-amino acid peptide hormone synthesized by the parathyroid glands, is essential for the maintenance of calcium homeostasis.While in its traditional metabolic role, PTH helps to maintain the serum calcium concentration within narrow, normal limits and participates as a determinant of bone remodeling, more specific actions, described as catabolic and anabolic are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), while the osteoanabolic effect of PTH is best seen when PTH or its biological amino-terminal fragment [PTH(1-34)] is used as a therapy for osteoporosis. These dual functions of PTH are unmasked under very specific pathological (PHPT) or therapeutic conditions. At the cellular level, PTH favors bone resorption, mostly by affecting the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL)-osteoprotegerin- RANK system, leading to an increase in osteoclast formation and activity. Increased bone formation due to PTH therapy is explained best by its ability to enhance osteoblastogenesis and/or osteoblast survival. The PTH-induced bone formation is mediated, in part, by a decrease in SOST/sclerostin expression in osteocytes. This review focuses on the dual anabolic and catabolic actions of PTH on bone, situations where one is enhanced over the other, and the cellular and molecular mechanisms by which these actions are mediated.

Fig. 1

The densitometric signature of primary hyperparathyroidism (PHPT) in the modern era. Bone densitometry at lumbar spine, femoral neck and radius in PHPT. Bone mineral density (BMD) is presented in comparison to expected values for normal controls. [Adapted from (7)].

Fig. 2

Microarchitectural features in pre-and post-menopausal women with primary hyperparathyroidism (PHPT). 3D micorcomputed tomography reconstructions of cancellous bone in pre- and post-menopausal women with PHPT (B and D), and normal controls (A and C). [Adapted from (8)].

Fig. 3

PTH as an anabolic agent for bone: a kinetic model. Treatment with PTH leads to increased bone turnover, with an early stimulation of bone formation followed later by a stimulation of bone resorption. It is thus formed an “anabolic window”, the period of time when PTH is maximally anabolic. When bone formation and resorption are stimulated, bone formation exceeds bone resorption, continuing the anabolic property of PTH. [Adapted from (45)]

Fig. 4

Microcomputed tomography images of iliac crest biopsies of postmenopausal women treated with either PTH(1–84) or teriparatide. A) Osteoporotic postmenopausal women treated with placebo or PTH(1–84) for 18 months. B) Paired biopsy specimens from a 64-yr-old woman before and after treatment with teriparatide for 36 months. [Adapted from (36, 37)].

Fig. 5

Anabolic and catabolic pathways of PTH on the skeleton. A) PTH decreases SOST/sclerostin expression in osteocytes. Sclerostin functions as a negative regulator of bone formation, and its downregulation by PTH contributes for the PTH-induced osteoanabolism. B) PTH favors bone resorption, mostly by increasing receptor activator of nuclear factor kappa-B ligand (RANKL) and decreasing osteoprotegerin (OPG) expression in osteoblasts, which ultimately leads to an increase in osteoclast formation and activity.