John P. Bilezikian

IGF-1 and Osteoporosis: Lessons from Mice and Men

The insulin-like growth factors (IGF-1 and -2) are ubiquitous polypeptides that mediate the activity of growth hormone. In many tissues they serve as paracrine or autocrine factors (1). Second only to the liver, the skeleton is an exceptionally rich source of IGF-1 where it is both synthesized and stored. During bone remodeling, both systemic and skeletal IGF-1 play a major role in the recruitment and differentiation of osteoblasts (2, 3). In the course of bone resorption, the initiating bone remodeling event, matrix-bound IGFs are released and become critical coupling agents linking the processes of bone resorption and bone formation (2). Efforts to establish a relationship between synthesis of rapid bone loss or impaired bone formation and changes in the skeletal or circulatory IGF system have led to several hypotheses suggesting that IGF-1 is of pathophysiologic significance (2). Two recent studies, one showing an age-associated decline in skeletal IGF-1, and the other relating serum IGF-1 to bone density, have strengthened the view that the skeletal IGF regulatory system is important in states of impaired bone remodeling (4, 5). Two additional studies have demonstrated a strong relationship between serum IGF-1 and bone mineral density in men with idiopathic osteoporosis (6, 7). Based on these lines of evidence and the concept that bone density at any age is strongly dependent on peak bone mass, our group has considered IGF-1 to be a key factor in the acquisition of peak bone mass. In this paper, data will be presented which suggest that in several inbred strains of mice and in humans, osteoporotic male idiopathic IGF-1 is an important determinant of bone mineral density (BMD).

CHAPTER 16 – Parathyroid Hormone: Structure, Function and Dynamic Actions

This chapter focuses on parathyroid hormone (PTH), which is an 84 amino acid hormone that regulates calcium homostasis via its actions on target tissues. Parathyroid hormone maintains serum calcium concentrations within a narrow physiological range by direct actions on bone and kidney tissue and an indirect action, via 1,25-dihydroxy vitamin D, on the intestinal tract. Parathyroid hormone release and gene expression, in turn, are regulated by serum calcium concentrations. Hypocalcemia stimulates the release of PTH from the parathyroid gland. Serum calcium concentrations increase by reabsorption of calcium in the distal convoluted tubule of the kidney or by ostoclast-mediated bone resorption. PTH also stimulates renal 1-α-hydroxylase activity in the kidney, which increases 1,25-dihydroxy vitamin D and enhances the intestinal absorption of calcium. These actions of PTH are mediated through a G protein-coupled receptor system in the cells of target tissues. A rise in extracellular calcium inhibits further secretion of parathyroid hormone. The gene that encodes PTH is representative of typical eukaryotic genes with consensus sequences for the initiation of RNA synthesis, RNA splicing, and polyadenylation. The human PTH gene has been localized to the short arm of chromosome 11 and is close to the calcitonin gene.

CHAPTER 46 – Primary Hyperparathyroidism

This chapter describes the clinical picture of primary hyperparathyroidism in the present scenario and the current status of bone markers in the investigation and management of this disorder. Primary hyperparathyroidism, one of the most common endocrine disorders, is characterized by hypercalcemia and elevated parathyroid hormone levels. The most common lesion found in patients with primary hyperparathyroidism is the solitary parathyroid adenoma, which accounts for 80% of cases. Identifiable risk factors in the development of parathyroid adenoma include a history of neck irradiation and prolonged use of lithium therapy for affective disorders. Despite the absence of radiologically evident bone disease, modern day primary hyperparathyroidism has a clearly defined pattern of skeletal involvement. The diminution of cortical bone and preservation of cancellous bone documented in bone mineral density studies and histomorphometry are associated with increases in bone turnover. Increases in both bone formation and resorption are reflected in increased levels of bone turnover markers. Data on the role of certain cytokines as potential mediators of skeletal effect in primary hyperparathyroidism continue to provide insights into the pathogenesis of this important metabolic bone disease.

Parathyroid Hormone as a Therapy for Osteoporosis

Parathyroid hormone (PTH) classically causes bone resorption and bone loss. However, since 1929 (1), it has been known that PTH can also have an anabolic effect on the skeleton. This salutary effect of PTH is the basis for the idea that PTH has the potential to become a therapy for osteoporosis. This chapter will review the effects of endogenous PTH, including lessons learned from primary hyperparathyroidism and the rationale for PTH therapy in osteoporosis. Clinical trials of PTH in osteoporosis, both alone and in combination with other drugs, will also be reviewed.