Calcium and Bone Disease PDF

CALCIUM and Bone Disease Reinhold Vieth Dept of Laboratory Medicine and Pathobiology, and Department of Nutritional Sciences APRIL 3, 2024 CALCIUM Atomic wt= 40 g/mol Valence = +2 (a divalent cation); Bone Ca = TRICALCIUM PHOSPHATE 3.64% of...

CALCIUM and Bone Disease Reinhold Vieth Dept of Laboratory Medicine and Pathobiology, and Department of Nutritional Sciences APRIL 3, 2024 CALCIUM Atomic wt= 40 g/mol Valence = +2 (a divalent cation); Bone Ca = TRICALCIUM PHOSPHATE 3.64% of earth’s crust (5th most abundant element) Sea water contains about 400 mg/L (=10 mmol/L) NB: Milk contains 300 mg/L Serum calcium = 2.5 mmol/L) lCALCIUM IS COMMONLY MEASURED IN SERUM AND URINE, TO UNDERSTAND BONE DISEASE OR NEUROMUSCULAR PROBLEMS. lParathyroid Hormone (PTH) IS MEASURED IF CALCIUM IS ABNORMAL, TO HELP UNDERSTAND THE CAUSE OF THE CALCIUM DISORDER. lBONE MARKERS (eg Alkaline Phosphatase) PROVIDE INSIGHT ABOUT CELLULAR ACTIVITY AND HELP TO MONITOR ITS THERAPY Laboratory Testing for CALCIUM: Can measure TOTAL Serum Calcium as well as ionized Plasma Calcium Normal total =2.5 mmol/L Normal ionized Calcium =1.2 mmol/L Total Calcium = Protein Bound (45%) + Free ionic Calcium (45%) + Complexed Ca (10%) eg Ca citrate Protein-bound calcium is inactive, i.e. not biologically available for membranes or bone, and its level is not regulated.  Why is calcium important in biology? Key factor in the stability of biological membranes Subcellular signalling Key component of Bone Lipids in biological membranes align Water- themselves in a Soluble monolayer at an oil- Choline water interface. The inner and outer parts of the cell are aqueous solutions Fat separated by the cell Soluble membrane, a bilayer of Palmitic Phospholipids. acid From R Stein. Nerve and Muscle, Plenum Press 1980. (S-135) The lipid bilayer of cell membranes  Calcium ions stabilize the cell membrane. Cations are linked to the negatively charged phorsphoric part of the phospholipids that comprise the membrane. This “anchors” them, and causes the cell membrane to be firmer, and less permeable to other substances. Calcium makes excitable membranes more resistant to depolarization. (Depolarization = signal for muscle contraction) -60 mV  With Low Ca Low Ca High Ca neurons fire more readily because ion leakage increases need for active Na transport, this lowers the threshold voltage for firing i.e., –60 mV voltage becomes higher as a % of threshold With Low Ca neurons fire more readily because ion leakage increases need for active Na transport, this lowers the threshold voltage for firing  Why is calcium important in biology? Key factor in the stability of biological membranes Subcellular signaling (huge cellular gradient): Intracellular Calcium = 1 MICRO-mol/L Extracellular “FREE” Calcium = 1 MILLI-mol/L Key component of the structural material, Bone The most tightly regulated thing in bloodstream (CV of Ca++ concentration =3%) Low Calcium => hyperexcitability of neuromuscular tissues: Chvostek Sign and Trousseau Sign  The primary purpose of bone is to be a reservoir of calcium. Therefore, the structural aspects of bone are the first to be compromised when there is a shortage of calcium.  Macroscopic Epiphysis Bone Growth: Shaft From Fetus to adult: Endochondral ossification Ossification begins in an area of preformed cartilage (C ). Distal ends of bone also Epiphyseal Fusion calcify (F), leaving a sparsely (stoppage of longitudinal mineralized region, the growth) epiphysial growth plate. After puberty, the growth plate also mineralizes, and longitudinal growth stops. Mountcastle 1661 Average Rate of Increase in Height cm / year – All due to BONE!! Cumulative Growth (Height) Epiphyseal Fusion (stoppage of longitudinal growth)  Alkaline Phosphatase normal range vs Age Note similarity with growth curve in orange.  Theory of remodeling Every month, an adult resorbs (dissolves away) about 1% of their bone, while reforming about 0.9% of their bone. NET RESULT, Every Year, an adult loses about 1% of their bone  Neck of Femur Vertebral Body Bone, sawn into cross-section, and PHOTOGRAPHED Cortical bone Trabecular bone As above, but X-RAY IMAGE  Theory of Cross-sectional drawing of a section of cortical bone, stained to highlight remodeling the canaliculi, that contain protoplasmic extensions of osteocytes. Haversian Canal STEP 1 2 3 4 5 6 1 Br J Pharmacol. 2021;178:1891– Endocrinology: The study of Biological Control Systems, whereby signalling molecules act via the circulation.  Three hormones serve to regulate ionized Calcium in the blood: lParathryoid hormone (PTH) lCalcitonin (CT) lAnd Calcitriol ( 1,25(OH)2D )  Overview of Endocrine Control of Calcium Example of a biological control system Calcitonin (CT) Bone formation Bone resorption Ca PTH Renal Ca reabsorption 1,25(OH)2D Intestinal Ca absorption Three hormones, PTH, CT, and 1,25(OH)2D serve the purposes of calcium regulation  Endocrinology: The study of Biological Control Systems that act via the circulation. Normal Feedback Regulation: PTH serves the purpose of CALCIUM regulation. Circulating THIS IS AN EXAMPLE OF PTH A NEGATIVE FEEDBACK LOOP: where the aim is to normalize back to a setpoint Ionized Calcium Set-point  INTERPRETING LAB TEST RESULTS Parathyroid Hormone (PTH) vs Calcium in Health and Disease Situations Kidney Plasma PTH (pmol/L) Disease: Parathyroid Primary OK Hyperparathyroid 14 7 Primary HYPOPARA- H ea THYROIDISM lth Parathyroid OK, but cancer? 0 2.5 mmol/L 5 Total Serum Calcium = “Free” + Protein Bound = 1 + 1.5 approx  CALCIUM FROM FOOD Only a fraction of the calcium you eat actually leaves the intestinal tract. What if you consume 1000 mg (1 g) in one day ? Eat 1000 mg Ca Absorb 200 mg Pass 800 mg to Stool Excrete 200 mg to Urine NORMAL BONE What if you take 400 mg (0.4 g) in a day ? IF ENOUGH VITAMIN D: BUT if Eat Ca 0.4 g/day 400 mg Absorb 200 mg (IF enough vit D you turn on Ca 0.2 g/day machinery to absorb calcium better) Pass 200 mg to Stool Excrete 200 mg to Urine NORMAL BONE What if you take 400 mg (0.4 g) in a day ? IF NOT ENOUGH VITAMIN D: BUT if Eat Ca 0.4 g/day 400 mg Absorb Ca = Absorb 200 mg (IF NOT ONLY 0.1 g/day enough vit D = Ca 0.3 g/day POOR Ca ABSORPTION) Pass 300 mg to Stool Excrete 100 mg to Urine = LOW BONE DENSITY Osteoporosis: The Human Skeleton: Note two types bone structures, with two support functions: prevent vertical collapse -to prevent bending. Bone is a structurally-self-engineering biomaterial Neck of Femur Vertebral Body Normal Mild Osteoporosis Severe Osteoporosis “Normal” bone density vs Age Important: Understand t-scores Z-Score t-score t-score Vs SAME GROUP VS DIFFERENT (Young) +2.5 ZERO>> -2.5 Age: 35 60 80 Osteoporosis diagnosis = bone density that is -2.5 SD below mean of adults < age 35 A t-score compares you This is a Z-score of -2.5 if