1. More Ch. 6 6.5 – 6.10 Bone Growth, Composition and Conditions

2. Ossification Skeleton begins to form in embryo at 6 week During all future development bone undergoes increases in size and ossification o Ossification = bone formation o Calcification = deposition of calcium o Endochondral ossification = bone replaces cartilage that was already presesnt o Intramembranous ossification = bone develops directly from connective tissue Bone growth continues through adolescence, and on average until about age 25 Toes “done” by age 11; pelvis and wrists may still be growing at 25. Lots of growth happens in relation to puberty hormones

3. Endochondryal Ossification Chondros = cartilage Endo = inside Most bones start as hyaline cartilage and are “models of adult bone” size and shape Cartilage gradually replaced by bone Time line: “This is an essay; timeline and pictures that follow” o 6 weeks proximal end of limb bone present but as hyaline cartilage o New cartilage on outer surface o Cells at center enlarge, blood vessels grow o Primary ossification starts and spread toward ends o Increases in length and in diameter o Centers of epiphyses calcify and become spongy bone o Cap of cartilage remains at articulation o Region of cartilage between epiphysis and diaphysis = lengthening bone

4. Figure 6-10 Endochondral Ossification (Step 1-7) As the cartilage enlarges, chondrocytes near the center of the shaft increase greatly in size. The matrix is reduced to a series of small struts that soon begin to calcify. The enlarged chondrocytes then die and disintegrate, leaving cavities within the cartilage. Blood vessels grow around the edges of the cartilage, and the cells of the perichondrium convert to osteoblasts. The shaft of the cartilage then becomes ensheathed in a superficial layer of bone. Blood vessels penetrate the cartilage and invade the central region. Fibroblasts migrating with the blood vessels differentiate into osteoblasts and begin producing spongy bone at a primary ossification center. Bone formation then spreads along the shaft toward both ends. Remodeling occurs as growth continues, creating a medullary cavity. The osseous tissue of the shaft becomes thicker, and the cartilage near each epiphysis is replaced by shafts of bone. Further growth involves increases in length and diameter. Medullary cavity Metaphysis Medullary cavity Primary ossification center Superficial bone Spongy bone Blood vessel Bone formation Diaphysis Epiphysis Hyaline cartilage Enlarging chondrocytes within calcifying matrix Capillaries and osteoblasts migrate into the epiphyses, creating secondary ossification centers. Soon the epiphyses are filled with spongy bone. An articular cartilage remains exposed to the joint cavity; over time it will be reduced to a thin superficial layer. At each metaphysis, an epiphyseal cartilage separates the epiphysis from the diaphysis. This light micrograph shows the ossifying surface of an epiphyseal cartilage. The pink material is osteoid, deposited by osteoblasts in the medullary cavity. On the shaft side of the epiphyseal cartilage, osteoblasts are continuously invading the cartilage and replacing it with bone. On the epiphyseal side, new cartilage is continuously being added. The osteoblasts are therefore moving toward the epiphysis, which is being pushed away by the expansion of the epiphyseal cartilage. The osteoblasts won’t catch up to the epiphysis, as long as both the osteoblasts and the epiphysis “run away” from the primary ossification center at the same rate. Meanwhile, the bone grows longer and longer. Hyaline cartilage Epiphysis Metaphysis Periosteum Compact bone Articular cartilage Spongy bone Epiphyseal cartilage Diaphysis Epiphyseal cartilage matrix Cartilage cells undergoing division and secreting additional cartilage matrix Medullary cavityOsteoblastsOsteoid LM  250 Secondary ossification center

5. Figure 6-10 Endochondral Ossification (Step 1-4) As the cartilage enlarges, chondrocytes near the center of the shaft increase greatly in size. The matrix is reduced to a series of small struts that soon begin to calcify. The enlarged chondrocytes then die and disintegrate, leaving cavities within the cartilage. Blood vessels grow around the edges of the cartilage, and the cells of the perichondrium convert to osteoblasts. The shaft of the cartilage then becomes ensheathed in a superficial layer of bone. Blood vessels penetrate the cartilage and invade the central region. Fibroblasts migrating with the blood vessels differentiate into osteoblasts and begin producing spongy bone at a primary ossification center. Bone formation then spreads along the shaft toward both ends. Remodeling occurs as growth continues, creating a medullary cavity. The osseous tissue of the shaft becomes thicker, and the cartilage near each epiphysis is replaced by shafts of bone. Further growth involves increases in length and diameter. Medullary cavity Metaphysis Medullary cavity Primary ossification center Superficial bone Spongy bone Blood vessel Bone formation Diaphysis Epiphysis Hyaline cartilage Enlarging chondrocytes within calcifying matrix

6. Figure 6-10 Endochondral Ossification (Steps 5-7) Capillaries and osteoblasts migrate into the epiphyses, creating secondary ossification centers. Soon the epiphyses are filled with spongy bone. An articular cartilage remains exposed to the joint cavity; over time it will be reduced to a thin superficial layer. At each metaphysis, an epiphyseal cartilage separates the epiphysis from the diaphysis. This light micrograph shows the ossifying surface of an epiphyseal cartilage. The pink material is osteoid, deposited by osteoblasts in the medullary cavity. On the shaft side of the epiphyseal cartilage, osteoblasts are continuously invading the cartilage and replacing it with bone. On the epiphyseal side, new cartilage is continuously being added. The osteoblasts are therefore moving toward the epiphysis, which is being pushed away by the expansion of the epiphyseal cartilage. The osteoblasts won’t catch up to the epiphysis, as long as both the osteoblasts and the epiphysis “run away” from the primary ossification center at the same rate. Meanwhile, the bone grows longer and longer. Hyaline cartilage Epiphysis Metaphysis Periosteum Compact bone Articular cartilage Spongy bone Epiphyseal cartilage Diaphysis Epiphyseal cartilage matrix Cartilage cells undergoing division and secreting additional cartilage matrix Medullary cavity Osteoblasts Osteoid LM  250 Secondary ossification center

7. An x-ray of growing epiphyseal cartilages (arrows) Epiphyseal lines in an adult (arrows) APPOSITIONAL GROWTH = Superficial layers of bone forms early in endochondral ossification New growth in the bones diameter results in layers – New lamella added in concentric rings around outside while inner layers are recycled

8. Intramembranous Ossification Osteoblasts differentiate o Fibrous connective tissue ( mesenchymal cells) o Matrix is created o Crystallization of calcium salts o Very active process requiring lots of nutrients o Osteoblasts  ossification  spicules form o Initially only spongy bone o Remodeling can lead to compact bone Creates dermal bones o Flat bones of skull, mandible (lower jaw), and clavicle (collar bone)

9. Blood and nerve supply to bones Bone maintenance and grow require blood supply Osseous tissue is highly vascular o Nutrient artery and vein: supply diaphysis, usually only one of each ( femur has more) o Enter through foramina – branch into smaller canals o Metaphyseal vessels – supply blood to cartilage that is or will be replaced by bone o Periosteal vessels – blood to periosteum and superficial osteons – branch during ossification o All are very interconnected Lymph – connect blood and lymph through osteons Nerves – travel along nutrient artery ( injuries to bones are very painful)

10. Remodeling Bone matrix constantly being recycled and renewed Used for both maintenance and changes to bone shape and structure Youth – recycle about 1/5 of calcium salts per year; more likely in areas of spongy bone Heavy metals are dangerous because they can be incorporated into bone – stay in circulatory system for many years. (Chernobyl Nuclear reactor leak; 1986 Ukraine, only other level 7 leak is Fukushuma Daiichi in 2011)

11. Impact of Exercise on bones “stresses” on mineral crystals cause bone growth Increases in muscle mass increase both weight and tension on bones = growth Ridges and bumps on bone relate to pull of tendons, diameter of bone relates to mass – non-athletes have more fragile bones (osteoporosis and arthritis) A broken leg with no stress, can lose 1/3 mass while using crutches ? Bedridden and paralyzed

12. Impact of Hormones on bones Calcitrol: o made by kidneys o increases absorption of Ca and PO4 in digestive tract Growth hormone o Made by pituitary o Stimulates osteoblast and synthesis of matrix Thyroxine o Thyroid o Also stimulates osteoblasts and synthesis of matrix Estrogen/ androgens o Ovaries and testes o Stimulates osteoblasts o Estrogen closes epiphysis earlier than androgens Parathyroid hormone o Parathyroid glands o Stimulates osteoclasts and osteoblasts o Increases Ca level in body fluids Calcitonin o Thyroid gland o Inhibits osteoclasts o Reduces Ca in body fluids o Triggers kidneys to loose calcium

13. Impact of Nutrition on bones Dietary sources of calcium and phosphate are required for healthy bone growth and maintenance Also required are: magnesium, fluoride, iron and manganese Vitamin C is needed for enzymatic reaction that makes cartilage Vitamin D is required for calcitrol to cause intestinal absorption of Ca and PO4 Vitamins A, K and B12 are also needed for normal bone growth

14. Nutrition and Calcium Bones are a mineral reservoir o 1-2 Kg of calcium ( 2.2 – 4.4 lbs) in body o 99% is in the bones Calcium levels are important for many functions: o Permeability of plasma membranes o Firing of nerve impulses o Contraction of muscle fibers o Widely varying ion concentrations can result in seizures or death o “electrolytes”

15. Figure 6-16a Factors That Alter the Concentration of Calcium Ions in Body Fluids Bone ResponseIntestinal ResponseKidney Response Parathyroid Gland Response Factors That Increase Blood Calcium Levels These responses are triggered when plasma calcium ion concentrations fall below 8.5 mg/dL. Low Calcium Ion Levels in Plasma (below 8.5 mg/dL) Low calcium plasma levels cause the parathyroid glands to secrete parathyroid hormone (PTH). Osteoclasts stimulated to release stored calcium ions from bone Osteoclast Bone Rate of intestinal absorption increases Kidneys retain calcium ions PTH more calcitriol Calcium released Calcium absorbed quickly Calcium conserved Decreased calcium loss in urine ↑ Ca 2+ levels in bloodstream

16. Figure 6-16b Factors That Alter the Concentration of Calcium Ions in Body Fluids Bone Response Intestinal Response Kidney Response Thyroid Gland Response Factors That Decrease Blood Calcium Levels These responses are triggered when plasma calcium ion concentrations rise above 11 mg/dL. HIgh Calcium Ion Levels in Plasma (above 11 mg/dL) Parafollicular cells (C cells) in the thryoid gland secrete calcitonin. Osteoclasts inhibited while osteoblasts continue to lock calcium ions in bone matrix Bone Rate of intestinal absorption decreases Kidneys allow calcium loss Calcitonin less calcitriol Calcium stored Calcium absorbed slowly Calcium excreted Increased calcium loss in urine ↓ Ca 2+ levels in bloodstream

17. Fractures Crack or break in bone Often from stress in unusual direction Need blood supply and portions of endosteum and periosteum in order to survive Repair: o Spongy bone forms o External callus of cartilage stabilizes bone o Cartilage is replaced by bone o Remodeling removes dead bone or extra layers Fracture types: o Transverse, displaced, compression, spiral, epiphyseal, communicated (shatter), greenstick

18. Figure 6-17 Types of Fractures and Steps in Repair Fractures are named according to their external appearance, their location, and the nature of the crack or break in the bone. Important types of fractures are illustrated here by representative x-rays. The broadest general categories are closed fractures and open fractures. Closed, or simple, fractures are completely internal. They can be seen only on x-rays, because they do not involve a break in the skin. Open, or compound, fractures project through the skin. These fractures, which are obvious on inspection, are more dangerous than closed fractures, due to the possibility of infection or uncontrolled bleeding. Many fractures fall into more than one category, because the terms overlap. Transverse fractures, such as this fracture of the ulna, break a bone shaft across its long axis. Displaced fractures produce new and abnormal bone arrangements; nondisplaced fractures retain the normal alignment of the bones or fragments. Compression fractures occur in vertebrae subjected to extreme stresses, such as those produced by the forces that arise when you land on your seat in a fall. Spiral fractures, such as this fracture of the tibia, are produced by twisting stresses that spread along the length of the bone. Immediately after the fracture, extensive bleeding occurs. Over a period of several hours, a large blood clot, or fracture hematoma, develops. An internal callus forms as a network of spongy bone unites the inner edges, and an external callus of cartilage and bone stabilizes the outer edges. PeriosteumSpongy bone of external callus Fracture hematoma Bone fragments Dead bone REPAIR OF A FRACTURE TYPES OF FRACTURES Transverse fracture Displaced fracture Spiral fracture Compression fracture Epiphyseal fracture Comminuated fracture Greenstick fracture Colles fracture Pott’s fracture A Pott’s fracture occurs at the ankle and affects both bones of the leg. A Colles fracture, a break in the distal portion of the radius, is typically the result of reaching out to cushion a fall. In a greenstick fracture, such as this fracture of the radius, only one side of the shaft is broken, and the other is bent. This type of fracture generally occurs in children, whose Long bones have yet to ossify fully. Comminuted fractures, such as this fracture of the femur, shatter the affected area into a multitude of bony fragments. Epiphyseal fractures, such as this fracture of the femur, tend to occur where the bone matrix is undergoing calcification and chondrocytes are dying. A clean transverse fracture along this line generally heals well. Unless carefully treated, fractures between the epiphysis and the epiphyseal cartilage can perman- ently stop growth at this site. The cartilage of the external callus has been replaced by bone, and struts of spongy bone now united the broken ends. Fragments of dead bone and the areas of bone closest to the break have been removed and replaced. A swelling initially marks the location of the fracture. Over time, this region will be remodeled, and little evidence of the fracture will remain. External callus External callus Internal callus

19. Diseases and Disorders Osteopenia = inadequate ossification o Aging ; begins between 30 and 40 o Lose 3% per decade o Vertebrae and jaw lose mass faster - spinal issues and loss of teeth Osteoporosis – enough bone is lost to compromise normal function o Also related to decreasing estrogen and androgens o More of an issue in women because of menopause Cancers