A group of researchers is developing new drugs for osteoporosis. They are testing a new drug, Substance X, that exhibits the following metabolic effects when given via an infusion in varying doses (as shown in the graphs below). Which of the following most closely resembles the metabolic effects of Substance X?

Question

A group of researchers is developing new drugs for osteoporosis.  They are testing a new drug, Substance X, that exhibits the following metabolic effects when given via an infusion in varying doses (as shown in the graphs below).  Which of the following most closely resembles the metabolic effects of Substance X?

Quizplus · Accepted Answer

11ec160b_3cf6_a10a_9249_23dab7f95d3b_MD0001_00 This investigational drug causes a dose-dependent increase in serum calcium and urine phosphate excretion, which resembles the activity of parathyroid hormone (PTH). PTH receptors are located on osteoblasts (not osteoclasts), and activation causes osteoblasts to increase production of receptor activator of nuclear factor kappa-B ligand (RANK-L) and monocyte colony-stimulating factor. These factors stimulate osteoclastic precursors to differentiate into bone-resorbing osteoclasts. PTH also decreases the release of osteoprotegerin (OPG), a decoy receptor for RANK-L; therefore, lower levels of OPG allow for more interaction between RANK-L and the osteoclastic receptor, increasing bone resorption and releasing calcium and phosphate into circulation. In the kidney, PTH decreases tubular reabsorption of phosphorus while increasing reabsorption of calcium. Therefore, the combined effects are increased serum calcium and urine phosphate levels. Chronically high levels of PTH (ie, hyperparathyroidism) increase the risk of osteoporosis. However, intermittent administration of recombinant PTH analogs induces a greater increase in osteoblast activity in proportion to osteoclast activity and a net increase in new bone formation. Teriparatide is a recombinant PTH analog used to treat osteoporosis. (Choice A) PTH increases renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which increases intestinal absorption of calcium and phosphate and decreases PTH secretion via negative feedback. 1,25-dihydroxyvitamin D analogs (eg, calcipotriol) can raise serum calcium to some extent, but suppression of PTH limits the degree of phosphate excretion in the urine. (Choice B) PTH increases renal phosphate excretion by inducing internalization and destruction of type IIa sodium/phosphate cotransporters (NPT2) in the proximal renal tubule. Fibroblast growth factor 23 (FGF23) is a hormone produced by osteocytes that acts synergistically with PTH to increase phosphate excretion by downregulating NPT2 gene expression. Investigational FGF23 inhibitors reduce renal phosphate excretion. (Choices C and D) Bisphosphonates (eg, alendronate, risedronate) are pyrophosphate analogs that attach to hydroxyapatite binding sites on bone surfaces and inhibit osteoclast-mediated bone resorption. Denosumab is a monoclonal antibody that decreases bone resorption by binding to RANK-L and blocking the interaction between RANK-L and RANK on osteoclast surfaces. These agents generally lower, rather than raise, serum calcium levels. Educational objective: Parathyroid hormone (PTH) causes increased bone resorption, increased serum calcium levels, and increased renal phosphate excretion. Chronically high levels of PTH increase the risk of osteoporosis. However, intermittent administration of recombinant PTH analogs (eg, teriparatide) induces a greater increase in osteoblast activity in proportion to osteoclast activity and a net increase in bone formation.

A Group of Researchers Is Developing New Drugs for Osteoporosis