Skeletal Pathology (Normal + MBD)

Describe the organization of collagen fibers in woven and lamellar bone.

- Woven bone has disorganized fibers

- Lamellar bone has fibers that are laid down in lamellae.

Describe the speed with which woven and lamellar bone are produced.

- Woven bone is produced quickly

- Lamellar bone is produced slowly

What are osteocytes?

- Osteoblasts that get entirely surrounded by bone, and no longer actively synthesize the bone

Describe the capabilities of osteocytes to detect their environment.

- Osteocytes have longer cell processes that can detect changes in the local microenvironment ('pizoelectric forces')

What is the function of osteoclasts?

- To take away bone

What is an osteon?

- This is the functional unit of bone; They are cylindrical structures with a central vascular canal (haversian canal)

Where are osteons found in the bone?

- Primarily found in the cortices

Bone is a richly vascular organ that is dynamic. How is the directionality of osteons modified?

- Process of remodeling

What is an osteoid seam?

- This is the initial layer of osteoid produced by an osteoblast

Describe what a normal and an abnormal osteoid seam may look like/how it develops.

- In normal situations, this is a thin layer (e.g. few microns thick) that is rapidly mineralized to become bone.

- Osteoid seams are thickened in animals that do not mineralize their bones appropriately (e.g., Rickets)

Describe the structure of cortical (compact) bone.

- Very dense and osteon-rich

Where is trabecular bone found?

- Found in the medullary cavity

Which has a greater surface area, trabecular or cortical bone? Which is covered by an endosteal envelope?

- The surface area of trabecular bone is exponentially greater than cortical bone and is covered by an endosteal envelope.

What are the two ways in which bone forms?

- Membranous ossification

- Endochondral ossification

Describe the process of membranous ossification.

- Direct transition from primitive mesenchymal cell to osteoblast to deposition of bone

What types of bones is membranous ossification responsible for the development of?

- Flat bone development

- Width expansion of long bones

What types of bones is endochondral ossification responsible for the development of?

- Most of the longitudinal growth in long bones

Describe the process of endochondral ossification.

- The cartilage proliferates and produces new cartilage, and subsequently the cartilage matrix mineralizes with chondrocyte death, vascular ingrowth, and bone that is deposited on top of the mineralized cartilage.

A developing bone that is formed entirely of cartilage is initially vascularized in the diaphyseal region and this becomes the ______________________________. After this happens, blood vessels grow into epiphyseal regions becoming _______________________________. What are the physes?

- Primary center of ossification

- Secondary center of ossification

- The physes are simply those regions between the two centers of ossification where endochondral ossification is actively occurring.

Describe the fates of the primary and secondary centers of ossification in endochondral ossification.

- The primary center of ossification will eventually ossify entirely

- The edges of the secondary of ossification never entirely ossify (this is because some cartilage must be 'left behind' as the articular surface)

What is the region of ossification beneath an articular surface called? What disease process is this relevant to?

- Articular Epiphyseal Complex

- Where osteochondrosis dissecans manifests

Disruption in what kind of ossification is the basis for osteochondrosis dissecans?

- Endochondral ossification

What is Wolff's Law?

- "Bone will adapt to loading patterns"

- This means that where bone isn't used (or is placed under tension), then the bone is taken away by osteoclasts; Where bone is loaded (or placed under compression) then additional bone is added by osteoblasts

What is the term for "Wolff's law in action"?

- Modeling

What is modeling of a bone?

- A change in size or shape that results from a loading pattern.

What is a "cutting cone"? What process is it responsible for?

- The bone biology equivalent of a drill, with osteoclasts at the head of the drill bit, followed by osteoblasts that replace the resorbed bone

- Remodeling

What are the differences between modeling and remodeling.

In modeling, bone can be ONLY added or ONLY removed, whereas in remodeling both processes can occur.

In remodeling, the sequence is always the same. What are the steps of the process?

- Activation -> Osteoclastic resorption -> Reversal and formation

Lesions of metabolic bone disease often affect one or multiple bones?

- Often affect multiple bones, sometimes to varying degrees and distributions

Metabolic bone disease is particularly important in captive ______________, and can in many cases be linked to problems relating to diet, husbandry, and/or renal disease.

- Reptiles

In all instances, moderate or severe metabolic bone disease is associated with risk of what?

- Risk of pathological fracture which should be distinguished from a primary traumatic (uncomplicated) fracture

What are osteoporosis and osteopenia?

- Ostoeporosis is a clinical disease associated with a reduction in bone mass

- Osteopenia reflects decreased bone mass not associated with clinical signs

Describe bones which are affected by osteoporosis (and osteopenia).

- Bones are brittle and fracture easily

Is osteoporosis a reversible change?

- Although this is potentially reversible in younger animals, lost trabecular bone in adults is slower to be replaced.

Gross changes associated with osteoporosis (and osteopenia) are most apparent in the _____________ bone.

- Trabecular

Describe the development/location of changes associated with osteoporosis (and osteopenia)

- Gross changes are most apparent in the trabecular bone, where plates of bone are replaced by 'struts'; 're-inforcement tracebculae' may also develop in an effort to maintain integrity.

- With time, the cortical bone becomes thin, porous and brittle.

- Microfractures accumulate and pathologic fractures can develop (particularly in sites where trabecular bone constitutes the main strength).

If the cause of osteoporosis (and osteopenia) is removed and growth resumes, what may be observed?

- Growth arrest lines might be seen

List causes of osteoporosis.

- Deficiency of trace elements (such as copper in ruminants)

- Starvation

- Disuse

- Glucocorticoids

- Declining estrogen levels (women; not in most veterinary species)

What is the typical pathogenesis of osteoporosis?

- Usually related to increased rate of resorption compared with rate of formation (i.e. in protein calorie malnutrition, resorption is normal and formation is decreased)

The distribution of osteoporosis lesions depends on cause. Indicate the distribution for each of the following causes:

A. Protein-calorie malnutrition

B. Disuse

C. Animals with orthopedic ('stress shielding')

A. Generalized

B. Regional

C. Localized

Why does localized osteoporosis develop secondary to orthopedic implants?

- Direct manifestation of Wolff's law (e.g., modeling in response to loading patterns)

What is osteomalacia also known as? What is it?

- Rickets

- Failure of mineralization

Rickets is a disease of the __________ skeleton and affects what sites?

- Growing

- Sites of endochondral ossification

Osteomalacia occurs in young or adult animals?

- Adults

What is the most important cause of osteomalacia?

- Deficiency of Vitamin D (absolute or effective)

While vitamin D deficiency is the most important cause of Rickets, what are some other causes/considerations?

- Phosphorus deficiency

- Fluorosis

- Xenobiotics that impair mineralization

- Less common, inherited forms in pigs, sheep, cats, and dogs

Describe the pathogenesis of how patients with renal disease develop osteomalacia.

- Vitamin D activation occurs in the kidney, and thus is reduced in patients with renal disease.

Does calcium deficiency cause osteomalacia in mammals?

- No

What are primary sources of vitamin D?

- Nutrition

- Exposure to UV radiation

There is some evidence that ______________ and _____________ might be particularly susceptible to vitamin D deficiency.

- Camelids

- Pigs

Describe the gross lesions of Rickets. They can be particularly prominent where?

- Thickened/flared metaphyses and elongated growth plates

- Particularly prominent at the costochondral junction

Describe the pathogenesis of the gross lesions associated with Rickets.

- These lesions reflect a failure of mineralization and subsequently endochondral ossification. Osteoclasts cannot bind to unmineralized matrix, resulting in reduced ability to remodel the bone and accumulation of microfractures.

In skeletally mature animals, histologic lesions of Rickets are only apparent where?

- Only apparent in newly formed bone ('widened osteoid seams')

Clinical signs associated with Rickets are related to what?

- Bone deformity

- Pathologic fracture

- Bone pain

Phenotypically, reptilian metabolic bone disease may have some combination of what two diseases? Making the distinction between these two can be challenging (and may not necessarily be helpful)

- Osteomalacia/Rickets

- Fibrous osteodystrophy

What are primary risk factors for Reptilian Metabolic Bone Disease?

- Inadequate UB light

- Inappropriate diet (e.g., low calcium, phosphate rich)

- Renal disease

What are clinical signs of reptilian metabolic bone disease?

- Pain (tremors, weakness) related to microfractures

- Bilaterally symmetric enlargement of the limbs

- Maxillary/mandibular enlargement

Describe the general pathogenesis of fibrous osteodystrophy.

- Pathologic levels of parathyroid hormone result in osteoclastic bone resorption and replacement with fibrous connective tissue

What are clinical manifestations of fibrous osteodystrophy in severe cases?

- Deformity (pliable bones)

- Pain

- Pathologic fractures

What are the possible causes of fibrous osteodystrophy?

- Primary hyperparathyroidism (idiopathic hyperplasia, parathyroid gland adenoma, pseudohyperparathyroidism)

- Nutritional secondary hyperparathyroidism

- Renal secondary hyperparathyroidism

In fibrous osteodystrophy, PTH acts on a receptor on _____________, which upregulate ______________ differentiation factor (RANKL) and down regulate ________________.

- Osteoblasts

- Osteoclast

- Osteoprotegrin

With primary hyperparathyroidism, what can occur due to a high calcium-phosphorus ratio?

- Tissue mineralization

Describe the pathogenesis of nutritional secondary hyperparathyroidism. Provide examples.

- Diets high in phosphorus cause a reciprocal decrease in calcium, resulting in persistently elevated PTH (ie. pure grain diets to pigs, all meat to cats/dogs, bran to horses).

Describe the pathogenesis of renal secondary hyperparathyroidism.

- Patients have impaired ability to excrete phosphorus, and reduced activation of Vitamin D. Ostoemalacia is precipitated by hypovitaminosis D and acidosis

Describe the gross appearance of fibrous osteodystrophy.

- Gross appearance can be variable depending on degree of resorption and fibrous/fibro-osseous proliferation

- Bone mass is reduces and trabeculae are thing

What is a "nickname" for dogs and horses suffering from fibrous osteodystrophy?

- Mandibular and maxillary bone can be particularly affected, giving the name "rubber jaw" in dogs and "big head" in horses (renal and nutritional secondary hyperparathyroidism, respectively)

Hypovitaminosis C (Scurvy) is an important disease of which veterinary species and why?

- Guinea pigs and non-human primates

- They lack L-gulono-γ-lactone oxidase and the ability to synthesize ascorbate which is required for hydroxylation of proline and lysine residues in procollagen, resulting in fragile collagen.

What are some signs/sequelae of hypovitaminosis C (Scurbvy)?

- Weakened vessels -> Hemorrhage

- Bone fragility

- Pathologic fractures

- Osteopenia

Hypervitaminosis A is associated with excessive what?

- Excessive retinoids (i.e. sweet potatoes, drugs)

What does hypervitaminosis A cause in skeletally immature animals and in adults?

- Skeletally immature animals -> Premature closure of growth plates and osteoporosis

- In adults, it tends to cause osteosclerosis, periosteal bone formation and exostoses.

What lesions does lead toxicosis lead to?

- Damage to osteoclasts leading to an osteosclerotic line ("lead line" parallel to the growth plate

- Laminar cortical necrosis in the brain (polioencephalomalacia)

- Acute tubular necrosis (nephrosis) within the kidney

Lead toxicosis lesions can mimic what other conditions in cattle and dogs?

- Cows -> BVDV

- Dogs -> CDV

In addition to lead toxicosis, what else can cause osteosclerosis?

- Chronic low level fluorosis

What is the mechanism for low level fluorosis leading to osteosclerosis?

- Fluoride is incorporated into hydroxyapetite, resulting in a substrate that is more resistant to resorption.

What does chronic high level fluorosis result in?

- Osteopenia

- Periosteal bone formation

- Hypomineralization of enamel can result from damage to ameloblasts and odontoblasts (grossly the teeth have chalky white enamel which may fracture easily)

What are causes of hypervitaminosis D?

- Calcinogenic plant ingestion (Solanum spp.)

- Ingestion of toxic levels of vitamin D

Animals with hypervitaminosis D may have dramatic ____________________________ at gross necropsy.

- Soft tissue mineralization

Chronic low dose Vitamin D ingestion is associated with what?

- Osteosclerosis

- Abnormal (basophilic) bone matrix

What is the pathogenesis of chronic low dose vitamin D ingestion?

- Suppressed bone resorption due to hypercalcemia and decreased PTH; vitamin D also directly stimulates osteoblasts