JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
March 2022
M-M08

Signalment (JPC #4002913):  12 week old cross breed pig

 

HISTORY:  Pigs in the herd experienced seizures, swollen joints, lameness, and weakness with muscle fasciculations followed by sudden death.

 

HISTOPATHOLOGIC DESCRIPTION:  Rib bone, costochondral junction:  The physeal cartilage is irregular and markedly thickened up to 10 times normal, and there are multiple islands/tongues of retained hypertrophic cartilage arranged in poorly organized columns that extend from the physis into the metaphysis and partially fill the medullary cavity (retention of hypertrophic cartilage). Chrondrocytes within these retained tongues are variably degenerate and occasionally lost. The islands of hypertrophic cartilage are often surrounded by light basophilic smudgy material (unmineralized osteoid), often lined by cuboidal osteoblasts and rarely osteoclasts in Howship’s lacunae. The primary spongiosa are disorganized, only occasionally oriented perpendicular to the physis, and have multifocal microfractures surrounded by areas of hemorrhage, fibrin, and edema. Medullary spaces in the metaphysis and to a lesser extent the diaphysis are often devoid of marrow elements and replaced by mesenchymal cells and fibrous connective tissue (medullary fibrosis).  The periosteum is markedly thickened up to 500um by fibrous connective tissue (periosteal fibrosis), and the cortex is markedly thinned.

 

MORPHOLOGIC DIAGNOSIS:  Rib bone, costochondral junction:  Failure of endochondral ossification with persistent metaphyseal tongues of hypertrophied chondrocytes, medullary fibrosis, periosteal fibrosis, and osteopenia (rickets), cross breed, porcine.

 

ETIOLOGIC DIAGNOSIS:  Nutritional osteodystrophy

 

CAUSE:  Vitamin D or phosphorus deficiency

 

CONDITION:  Rickets

 

GENERAL DISCUSSION:

• Rickets and osteomalacia refer to two conditions with similar pathogenesis and cause that differ in the age of the animal affected (rickets = young, osteomalacia = adult)
• In both conditions there is defective bone (osteoid) formation due to defective mineralization
• Additionally, in young animals with rickets there is a failure of endochondral ossification and failure of mineralization of the cartilage matrix at growth plates
• The two most common causes of rickets and osteomalacia are vitamin D deficiency and phosphorus deficiency; animals age, growth rate, cause, and duration all influence the nature and appearance of the lesions

 

PATHOGENESIS:

• Review of Vitamin D metabolism
• Vitamin D is biologically inert, requiring 2 subsequent hydroxylations in the body to become the active form, 1,25-dihydroxyvitamin D
• Vitamin D can be obtained in 2 forms – Vitamin D2 (ergocalciferol), present in yeasts and plants, and Vitamin D3 (cholecalciferol), present in fatty fish and produced in the skin from 7-dehydrocholesterol through the action of ultraviolet (UV) radiation; both D2 and D3 are then converted in the liver
• First hydroxylation step: in the liver, forms 25-hydroxyvitamin D; this is the major form of Vitamin D in circulation
• Second hydroxylation step: in the renal proximal tubular epithelium, via 1-alpha-hydroxylase, forms 1,25-dihydroxyvitamin D (active form of vitamin D)
• Activity of 1-alpha-hydroxylase is increased with increased PTH activity on renal proximal tubular epithelium, low phosphorus, and low calcium (indirectly through PTH stimulation)
• Vitamin D’s effects in the body:
• Downregulation of 1-alpha-hydroxylase activity in renal proximal tubular epithelium (negative feedback)
• Binds to vitamin D receptors in the nuclei of renal tubular epithelium and intestinal epithelium, increasing transcription and production of calcium-binding proteins such as calbindin -> results in significant increase in renal and intestinal absorption of calcium
• Complex and antagonistic interactions in bone, including upregulation of RANKL with increased bone resorption as well as increased osteoblast differentiation; unclear if its effects on bone mineralization are direct or due to effects on extracellular concentrations of calcium and phosphorus
• Normal endochondral ossification: Mineralization of cartilage matrix and osteoid deposited during bone remodeling is a critical event > hypertrophic chondrocytes degenerate and the narrow intercellular septa break down > capillary sprouts derived from metaphyseal vessels invade vacant lacunar spaces > osteoprogenitor cells accompany invading capillaries > osteoprogenitor cells differentiate into osteoblasts that deposit osteoid on spicules of mineralized cartilage > osteoid is ultimately mineralized to form bone (1^o spongiosa) > removal of calcified cartilage cores and remodeled resulting in mature lamellar bone (2^o spongiosa)
• Pathogenesis of rickets (failure of mineralization):
  • General abbreviated pathogenesis: Dietary Ca+ / P Deficiency > failure of mineralization of osteoid/cartilage > failure of endochondral ossification > retention of tongues of hypertrophic cartilage > decrease cortical mineralization > weakened bone > fractures
  • Details:
• Growth plate: Failure of mineralization of cartilage and lack of osteoprogenitors and osteoblasts > persistence of tongues of hypertrophic chondrocytes
• Trabecular bone: Failure of mineralization of osteoid > osteoclasts cannot bind to unmineralized matrix and cannot remodel > failure of bone and cartilage removal in cutback zones > impaired bone remodeling > thickened, irregular metaphyseal trabeculae covered by seams of unmineralized osteoid > trabecular microfractures and infractions > +/- development of fibrous osteodystrophy (particularly if hypocalcemia and secondary hyperparathyroidism develop)
• Cortical bone: Failure of mineralization of osteoid > endocortical and trabecular surfaces are thickened by wide seams of unmineralized osteoid > softened bone that is deformed by weight bearing > development of microfractures
• Causes of rickets/osteomalacia:
• Vitamin D deficiency: Most commonly caused by dietary deficiency; less common causes:
• Gastrointestinal malabsorption due inherited defects in vitamin D metabolism
• Type I vitamin D-dependent rickets (defect in 1-alpha-hydroxylase), an autosomal recessive trait in pigs and humans
• In grazing animals UV light-induced production of vitamin D is more important than dietary sources and may be reduced in winter months; dietary plant sources often have inadequate levels of vitamin D2
• Pregnancy and lactational demands may also contribute to osteomalacia under these conditions
• Type II vitamin D-dependent rickets (hereditary vitamin D-resistant rickets) (defect in 1,25-dihydroxycholecalciferol receptor-effector systems in target organs)
• Occurs in humans and marmosets, sporadic reports in dogs and cats
• High levels of 1,25-dihydroxycholecalciferol but deficiency in receptor > poor Ca and P absorption from the intestines > hypocalcemia and hypophosphatemia > severe rickets
• Phosphorus deficiency:
• Phosphorus is necessary for the formation of hydroxyapatite as well as for apoptosis of hypertrophic chondrocytes in the physis
• Uncommon but may occur in animals grazing low phosphorus pastures or if they have impaired intestinal phosphorus absorption; cattle are more susceptible than sheep and horses are resistant; unlikely to occur in carnivores except under unusual dietary circumstances; excess phosphorus more common and results in nutritional secondary hyperparathyroidism and fibrous osteodystrophy
• Hypophosphatemic vitamin D-resistant rickets (renal hypophosphatemic rickets) results from impaired renal reabsorption and intestinal absorption of P, and is inherited as an X-linked dominant trait in humans and mice
• Other causes:
• Dietary iron excess (experimentally-induced rickets in rats due to interference with phosphorus absorption)
• Dietary fluoride excess (i.e. fluorosis, M-T04; fluoride interferes with mineralization when incorporated into the bone matrix, resulting in lesions resembling osteomalacia in cattle)
• Ca deficiency causes rickets-like lesion in birds, but not mammals; uncomplicated Ca deficiency in mammals more likely to result in osteoporosis or fibrous osteodystrophy (M-M10, due to hyperparathyroidism)
• Low Ca levels may occur as part of vitamin D deficiency resulting in both rickets and concurrent fibrous osteodystrophy in growing animals

 

TYPICAL CLINICAL FINDINGS:

• Pain, lameness, stiffness, reluctance to stand, fractures, soft bones
• Varus or valgus deformity, retarded growth
• Hypophosphatemia, hypo/normocalcemia, increased alkaline phosphatase (bone isoenzyme)
• Cachexia and anemia in longstanding osteomalacia
• Phosphorus-deficient animals may demonstrate osteophagia and pica

 

TYPICAL GROSS FINDINGS:

• Lesions most prominent at sites of rapid growth where cartilage contributes most significantly to skeletal growth (e.g. ribs, ends of long bones); thickened metaphysis from lack of osteoid resorption (rachitic metaphysis); most prominent as well-defined knobs on the inner surface of ribs at costochondral junction (rachitic rosary)
• Enlarged joints because of flaring of metaphysis; spontaneous fractures
• Irregular thickening of physeal cartilage
• Varus and valgus limb deformities
• Kyphosis, lordosis, and scoliosis
• Deformations of the chest and mandibles; domed skull

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Rickets: Young animal with growth plate
• Growth plate (hallmark lesion): Marked increase in number of persistent hypertrophic chondrocytes forming disorganized clumps at sites of endochondral ossification – at the physis and in the epiphysis underlying the articular cartilage 
• Metaphysis: Disorganized primary spongiosa; unmineralized clumps of hypertrophic chondrocytes; thickened, irregular metaphyseal trabeculae covered by thick seams of unmineralized osteoid (need special stains/techniques to recognize unmineralized nature of thick osteoid seams); microfractures of trabeculae
• Cortex: Lesions more subtle than in growth plates and metaphysis; thickened cortex; unmineralized osteoid on periosteal surface; microfractures
• Osteomalacia: Adult animal, no growth plate involvement
• Increased matrix (unmineralized osteoid) at locations of mechanical stress on bone
• Thin, soft cortices; reduction in number/size of trabeculae; unmineralized osteoid may be present on trabeculae, cortical surfaces and in osteons; osteoporosis may be superimposed
• Expanded marrow cavity
• Increased fragility of bone; fracture sites vary depending on species
• Various skeletal deformities

 

DIFFERENTIAL DIAGNOSIS:

• Swelling of carpal and other joints due to enlarged ends of long bones may resemble arthritis
• Thickened physeal cartilage similar to that of rickets is seen in osteochondrosis (M-M21) in some species and in inherited dwarfism of Alaskan Malamute dogs, but lack the bone fragility and trabecular lesions seen in rickets
• Bone deformities in birds
• Tibial dyschondroplasia (M-T06): Retention of nonvascularized, unmineralized cartilage in the proximal metaphysis of the tibiotarsus and tarsometatarsus of rapidly growing birds; failure of chondrocytes to undergo complete hypertrophy
• Turkeys: Poult malabsorption syndrome results in angular limb deformities
• Chickens: Vitamin A toxicity results in thickened growth plates

 

COMPARATIVE PATHOLOGY:

• Susceptibility to vitamin D deficiency: Alpacas and llamas > sheep > cattle (also occurs in housed piglets and calves due to ration formulation errors and lack of sunlight)
• Susceptibility to P deficiency: Cattle > sheep >>> horses (also reported in farmed red deer, not recognized in piglets, and is virtually impossible in carnivores due to the high P levels normally present in their diets)
• Pigs: Vitamin D-dependent rickets, type I, is a familial disease inherited as an autosomal recessive disorder (deletion in CYP27B1 gene > defective 1-alpha-hydroxylase > cannot form 1,25-dihydroxycholecalciferol); severe lesions may develop in young rapidly growing piglets with vitamin D deficiency (dietary or sunlight defeciency)
• New World monkeys have higher circulating levels of active vitamin D, cannot utilize vitamin D2 (ergocalciferol), and require large amounts of D3 (cholecalciferol) (vitamin D-resistant rickets or VDRR)
• Have increased amounts of osteoid and increased osteoclastic resorption and may also demonstrate lesions of fibrous osteodystrophy and osteopenia
• Concurrent gastrointestinal disease may also play a role in development of bone disease (via impaired vitamin D, P, or Ca absorption)
• Cats: CYP27B1 gene (which encodes renal 1-alpha-hydroxylase) defect has been identified in individual cats; vitamin D deficiency rickets is rare in dogs and cats unless not being fed a commercial diet
• Foals: similar gross and histologic lesions as in other species; a recent case report suggested a pathogenesis of lack of sunlight and/or low dietary Vitamin D but could not rule out a genetic basis (Asin, J Vet Diagn Invest. 2021)
• Sheep: Corriedale sheep in New Zealand have a unique form of rickets with autosomal recessive inheritance, in addition to classic rickets lesions, also have:
  • Increased osteoclastic activity and resorption cavities within trabeculae (“dissecting osteitis”) due to hyperparathyroidism
  • Persistence of the primary spongiosa
  • Collapse of subchondral bone in the humeral head
  • Enthesophytosis around the tarsus, metacarpophalangeal and metatarsophalangeal, and proximal and distal interphalangeal joints
• Birds and reptiles: cannot fully utilize D2 and require UV light access or vitamin D3 supplementation
• Turkeys are more sensitive to low dietary D3 than are chickens
• Lesser hedgehog tenrecs: Recent report identifying osteomalacia of multiple bones in captive animals on Vitamin D-deficient, all insect diets (LaDouceur, Vet Pathol. 2020)

 

REFERENCES:

1. Asin J, Murphy BG, Samol MA, Polanco J, Moore JD, Uzal FA. Rickets in a Thoroughbred-cross foal: case report and review of the literature. J Vet Diagn Invest. 2021;33(5):987-992.
2. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis: Elsevier; 2016:60-63, 68-74.
3. Crespo R, Franca MS, Fenton H, Shivaprasad HL. Galliformes and Columbiformes. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:747, 767.
4. Hardcastle MR, Dittmer KE. Fibroblast growth factor 23: A new dimension to diseases of calcium-phosphorus metabolism. Vet Pathol. 2015;52(5):770-784.
5. Jones ME, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:119.
6. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, Ailuridae In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:230-231.
7. LaDouceur EEB, Murphy BG, Garner MM, Cartoceti AN. Osteomalacia With Hyperostosis in Captive Lesser Hedgehog Tenrecs (Echinops telfairi). Vet Pathol. 2020;57(6):885-888.
8. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:375.
9. Matz-Rensing KM, Lowenstine LJ. New World and Old World Monkeys. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:345.
10. Myers EA, Sander JE.   In: Boulianne M., ed. Avian Disease Manual. 8^th ed. Jacksonville, FL: American Association of Avian Pathologists; 2019:189-191, 202-203
11. Olson EJ, Carlson CJ. Bones, joints, tendons, and ligaments. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:981-982.
12. Olson EJ, Shaw GC, Hutchinson EK, et al. Bone disease in the common marmoset: Radiographic and histological findings. Vet Pathol. 2015;52(5):883-893.
13. Origgi FC. Lacertilia. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:874.
14. Pessier AP. Amphibia. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:926.
15. Pritzker KPH, Kessler MJ. Arthritis, muscle, adipose tissue, and bone diseases of non-human primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. Waltham, MA: Elsevier; 2012:661-663.
16. Schild CO, Boabaid FM, Olivera LGS, et. al. Osteomalacia as a result of phosphorus deficiency in beef cattle grazing subtropical native pastures in Uruguay. J Vet Diagn Invest. 2021;33(5):1018-1022.
17. Shivaprasad HL. Nutritional diseases.  In: Boulianne M., ed. Avian Disease Manual. 8^th Jacksonville, FL: American Association of Avian Pathologists; 2019:147,153.
18. Shivaprasad HL. Miscellaneous diseases.  In: Boulianne M., ed. Avian Disease Manual. 8^th Jacksonville, FL: American Association of Avian Pathologists; 2019:165,170-171.
19. Smith DA. Palaeognathae: Apterygiformes, Casuariiformes, Rheiformes, Struthioniformes, Tinamiformes. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:637-638.
20. Trupkiewicz J, Garner MM, Juan-Salles C. Passeriformes, Caprimulgiformes, Coraciiformes, Piciformes, Bucerotiformes, and Apodiformes. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:815.
21. Rodriguez CE, Henao Duque AM, Steinberg J, Woodburn DB. Chelonia. In: Terio K, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:832.

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