Bone Minerals Homeostasis PDF

Bone Minerals Homeostasis Aikseng Ooi, PhD. Room 132 [email protected] slide-1 Summary 1. Calcitriol, PTH and FGF23 are the principal regulators of serum calcium homeostasis 2. Calcitonin, glucocorticoids, and estrogen are secondary regulators of serum calcium homeostasis 3. Bones act as calc...

Bone Minerals Homeostasis Aikseng Ooi, PhD. Room 132 [email protected] slide-1 Summary 1. Calcitriol, PTH and FGF23 are the principal regulators of serum calcium homeostasis 2. Calcitonin, glucocorticoids, and estrogen are secondary regulators of serum calcium homeostasis 3. Bones act as calcium reservoir 4. There are non-hormonal regulators of calcium homeostasis 5. Bisphosphonates are analogues of pyrophosphates slide-2 Rickets is caused by vitamin D deficiency slide-3 J Clin Invest. 2006 Aug 1; 116(8): 2062–2072. UV exposure as a treatment for rickets slide-4 J Clin Invest. 2006 Aug 1; 116(8): 2062–2072. Vitamin D Deficiency is a very common problem Rickets (rare) Loss of bone density à osteoporosis and fracture Muscles weakness Autoimmune problems Diabetes Low testosterone in men slide-5 Serum Ca is principally controlled by 3 hormones 1.1,25(OH)2D3 2.Fibroblast growth factor 23 (FGF23) 3.Parathyroid hormone (PTH) slide-6 UV exposure synthesizes vitamin D Heat slide-7 BoneKEy Reports (2014) 3, Article number: 479 Conversion of vitamin D3 to the active calcitriol by CYP27B1 CYP2R1 CYP27B1 1,25(OH)2D3 Calcitriol slide-8 BoneKEy Reports (2014) 3, Article number: 479 The enzyme largely responsible is the this conversion. CYP2R1 as will be described in subsequent chapters.87 Discovery of vitamin D Fraser and Kodicek88 demonstrated HF DeLuca that the conversion of 25-OH-D3 to what was later identified by Holick et al.71,72 as 1,25-(OH)2D3 takes place in the kidney and, in particular, 89 the existence and t amounts in these tiss function of the vitam been firmly establish in the proximal convoluted tubule. It was The Vitamin D Endocrine System cloned as the case, subsequent ch CYP27B1 by three groups.90–92 autocrine functions o Following identification of 25-OH-D3, the organ responsible for With the advent of molecular biology, transcripts of the the conversion of vitamin D3 to 25-OH-D3 was determined to be During the course CYP27B1 have been found in several cells not previously the liver because subtotal hepatectomy largely eliminated D. Reports of recognized as a site of production of 1,25-(OH) DeLuca laboratory b 2 3 this conversion.86 The enzyme largely responsible is the the existence and the generation of 1,25-(OH) D in small 87 2 metabolism 3 the of CYP2R1 as will be described in subsequent chapters. amounts in these tissues have suggested a paracrine/autocrine Fraser and Kodicek88 demonstrated that the conversion function of the vitamin D system. This is likelydemonstrated true but has not that 71,72 of 25-OH-D3 to what was later identified by Holick et al. as been firmly established by rigorous chemicaldegree methods. of In any conversio 1,25-(OH)2D3 takes place in the kidney and, in particular, case, subsequent chapters will discuss the possible paracrine/ giving very high bloo autocrine functions of the vitamin D system. Low During the course of this development, high-calcium Ian Boyle in the diets a DeLuca laboratory became very interested invitamin the regulation D isofclearly the metabolism of vitamin D. In a classical paper, it was The beginning of a demonstrated that when a low-calcium diet is fed a high clear. Garabedian et degree of conversion of 25-OH-D3 to 1,25-(OH) 2D3 occurs, giving very high blood levels of 1,25-(OH)2Dwas when by th 3, whereas detected high-calcium diets are fed the synthesis of the active form of the parathyroid hor vitamin D is clearly suppressed producing low amounts.93,94 the 1a-hydroxylas The beginning of a feedback regulation of system became hypocalcemia clear. Garabedian et al.95 was able to show that When the parathyroi was detected by the parathyroid glands and, in response, to sense the hypoc the parathyroid hormone (PTH) proved to be the stimulus 1,25-(OH) D33.. Althou of the 1a-hydroxylase in the kidney to produce 1,25-(OH)22D When the parathyroids were removed, the animal was unable deduced, it is clear th to the sense theD-based hypocalcemia interpret it by producing Figure 3 A diagrammatic representation of vitamin endocrineand system. mechanism to stim slide-9 1,25-(OH) exact mechanism has yet to be 2D3. Although BoneKEy Reports (2014) 3,shown Article 479 The calcium-sensing proteins in the parathyroid and ‘C’ cells arethe asnumber: a of the 1a-hydroxylas deduced, it is clear that parathyroid acts through the G-protein thermometer. of PTHtothat signals the Figure 3 A diagrammatic representation of theSlight vitaminhypocalcemia D-based endocrinecauses system. secretion mechanism stimulate theCYP27B1 transcriptionthis and still translation remains as The calcium-sensing proteinstoinsynthesize the parathyroid and ‘C’ 2cells are shown a D3 that directsascalcium in the intestine, kidney and 1,25-(OH)2D3, and 1,25-(OH) of mobilization the 1a-hydroxylase enzyme to produce thermometer. Slight hypocalcemia causes secretion of PTH that signals the CYP27B1 very potent calciu bone. A feedback suppression of PTH synthesis secretion, parathyroid this still and remains as theand major regulator of synthesis of this to synthesize 1,25-(OH)2D3 that directs calcium mobilization in the intestine, kidney and 96 ‘endogenous Nicolaysen’s factor very potent calcium-mobilizing is parathyroid shown. Calcitonin is secreted by the ‘C’ cells ofhormone. the proliferation by 1,25-(OH) 2D3and bone. A feedback suppression of PTH synthesis and secretion, 52 ‘endogenous factor’ was clearly identified as the PTH/1, is shown. Calcitonin is secreted by theresorption. ‘C’ cells of the proliferation by 1,25-(OH)2D3 thyroid. It suppresses bone 25-(OH) 2D system. 52,94 Expression of CYP27B1 is controlled by parathyroid hormone (PTH) Catabolism of calcitriol by CYP24A1 counters its effects thyroid. It suppresses bone resorption. 25-(OH)2D system. CYP24A1 Figure 4 Degradation of 1a,25-(OH)2D3. The CYP24A1 gene is induced by 1,25-(OH)2D3. The resulting enzyme carries out all the reactions shown to produce the biologically 1,25-(OH) its own destruction inactive excretion product,slide-10 calcitroic acid. Presumably, a similar set of reactions takes place with 25-OH-D 3 as the substrate. 2D3 programs BoneKEy Reports (2014)Clearly, 3, Article number: 479 through the CYP24A1. BoneKEy Reports | JANUARY 2014 5 Whole body calcium turnover Schematic representation of the whole body daily turnover of calcium slide-11 3 Calcitriol promotes Ca2 and P release from bone PTH Ca2 and P release slide-12 J Clin Invest. 2006 Aug 1; 116(8): 2062–2072. 5/3/15 The PTH-D3 axis of calcium regulation Calcium Homeostasis and its regulation by PTH and calcitriol. PTH has stimulatory effects on bone and kidney, including the stimulation of 1α-hydroxylase activity in kidney mitochondria leading to the increased production of calcitriol, a biologically active metabolite of Vit D. slide-13 Low serum calcium condition Bone Remodeling cycle. slide-14 4 High serum calcium condition slide-15 Serum Ca and P are principally controlled by 3 hormones 1.1,25(OH)2D3 2.Fibroblast growth factor 23 (FGF23) 3.Parathyroid hormone (PTH) slide-16 The FGF23 axis of calcium regulation slide-17 slide-18 J Clin Invest. 2008 Dec 1; 118(12): 3820–3828. J Clin Invest. 2006 Aug 1; 116(8): 2062–2072. Non-calcium related function of calcitriol slide-19 J Clin Invest. 2006 Aug 1; 116(8): 2062–2072. Secondary hormonal regulators of bone mineral homeostasis 1. Calcitonin (CT) 2. Glucocorticoids 3. Estrogens slide-20 The enzyme largely responsible is the this conversion. CYP2R1 as will be described in subsequent chapters.87 Fraser and Kodicek88 demonstrated that the conversion of 25-OH-D3 to what was later identified by Holick et al.71,72 as 1,25-(OH)2D3 takes place in the kidney and, in particular, the existence and t amounts in these tiss function of the vitam been firmly establish case, subsequent ch autocrine functions o During the course DeLuca laboratory b the metabolism of Calcitonin (CT) Calcitonin (CT) suppresses kidney demonstrated that suppresses bone Ca++ reabsorption degree of conversio resorption giving very high bloo Low high-calcium diets a vitamin D is clearly The beginning of a clear. Garabedian et was detected by th the parathyroid hor of the 1a-hydroxylas When the parathyroi to sense the hypoc 1,25-(OH)2D3. Althou deduced, it is clear th Figure 3 A diagrammatic representation of the vitamin D-based endocrine system. mechanism to stim slide-21 BoneKEy and Reports (2014) Articleasnumber: The calcium-sensing proteins in the parathyroid ‘C’ cells are3,shown a of479 the 1a-hydroxylas thermometer. Slight hypocalcemia causes secretion of PTH that signals the CYP27B1 this still remains as to synthesize 1,25-(OH)2D3 that directs calcium mobilization in the intestine, kidney and very potent calciu bone. A feedback suppression of PTH synthesis and secretion, and parathyroid ‘endogenous factor proliferation by 1,25-(OH)2D3 is shown. Calcitonin is secreted by the ‘C’ cells of the thyroid. It suppresses bone resorption. 25-(OH)2D system.52 Calcitonin suppresses bone resorption Calcitonin lowers serum Ca and P – Principal actions are to lower serum calcium and phosphate. – Inhibits bone resorption (osteoclasts), but over time affects bone formation (long-term prevents remodeling). – Inhibits both calcium and phosphate reabsorption in the kidney. – Generally antagonistic to PTH. slide-22 Glucocorticoids 1. A steroid hormone 2. Antagonize vitamin D-stimulated intestinal calcium transport 3. Stimulate renal calcium excretion 4. Block bone collagen synthesis 5. May increase PTH-stimulated bone resorption 6. Useful for reversing hypercalcemia in diseases that produce 1,25[OH]2D (lymphomas) or in cases of 1,25[OH]2D intoxication 7. Glucocorticoids induce osteoblast apoptosis. slide-23 Estrogen Reduces bone resorbing action of PTH Principal use is postmenopausal osteoporosis Inhibits osteoclasts and promotes osteoblasts survival slide-24 Nonhormonal Agents 1. Bisphosphonates 2. Calcimimetics 3. Plicamycin (Mithramycin) 4. Thiazides 5. Fluoride 6. Strontium Ranelate 7. SERM (selective estrogen receptor modulator) slide-25 5/3/15 Bisphosphonates Actonel (risedronate sodium) HO O OH O P C P OH CH2 OH N slide-26 ONa Bisphosphonates 1. Two classes of bisphosphonates – Nitrogen containing and non-nitrogen containing 2. Non-nitrogen containing (i.e. clodronate, tiludronate, and etidronate) acts by incorporating into ATP 3. Nitrogen containing class (i.e. pamidronate, alendronate, ibandronate, risedronate, and zoledronate) acts by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway. 4. Nitrogen containing class is more potent. slide-27 Nitrogen containing bisphosphonates slide-28 Drug Des Devel Ther. 2011; 5: 445–454. Bisphosphonates pharmacokinetics Less than 10% is absorbed Absorption is further reduced when taken with food Causes gastric irritation (lower in etidronate) ~50% of absorbed bisphosphonates accumulate in bone ( can remain there for months) Unbound bisphosphonates excrete in the urine slide-29 Calcimimetics Cinacalcet Activates calcium sensing receptor (CaR) Blocks PTH secretion Useful for treating secondary hyperparathyroidism in chronic kidney disease and parathyroid carcinoma slide-30 Plicamycin (Mithramycin) Cytotoxic antibiotic Use as treatment for Paget’s disease and hypercalcemia Blocks transcription Unclear mechanism of action slide-31 Raloxifene 1. SERM (selective estrogen receptor modulator) 2. Selectively activate estrogen receptor on bones 3. Antiestrogenic on uterus and on breast 4. Promotes blood coagulation slide-32 Parathyroid hormone (PTH) PTH in low and intermittent doses may increase bone formation without stimulating bone resorption. Teriparatide (Forteo®)- osteoporosis – Segment of PTH (recombinant form of PTH 1-34) – Stimulates new bone formation – Injected daily, 20 μg – Caution: Osteosarcoma in rats slide-33 Prolia (Denosumab) First FDA-approved RANK Ligand inhibitor A human IgG2 monoclonal antibody with affinity and specificity for human RANKL, MW: 147 kDa; inhibiting osteoclast formation, function, and survival Post menopausal osteoporosis Significantly reduce fractures of the spine, hip and other bones 2 shots a year, increases bone density Side effects: Hypocalcemia; infections (skin, bladder, lower abdomen and ear); skin inflammation/rash; jaw bone problem (osteonecrosis); unusual thigh bone fractures slide-34 Summary 1. Calcitriol, PTH and FGF23 are the principal regulators of serum calcium homeostasis 2. Calcitonin, glucocorticoids, and estrogen are secondary regulators of serum calcium homeostasis 3. Bones act as calcium reservoir 4. There are non-hormonal regulators of calcium homeostasis 5. Bisphosphonates are analogues of pyrophosphates slide-35