Fibrous osteodystrophy is a disease of bone metabolism caused by excessive production of parathyroid hormone (PTH). Hyperparathyroidism can have different etiologies, all leading to excessive demineralization of bone tissue, with ensuing fibrous swelling, deformities, and fractures of bone:
Disease of the parathyroid glands with excessive production of PTH leads to primary hyperparathyroidism.
Chronic renal disease that is often associated with mineral imbalances such as hyperphosphatemia, leads to counterregulatory hyperparathyroidism, also termed renal secondary hyperparathyroidism.
Nutrient deficiencies with inadequate calcium and/or excessive phosphorus can cause nutritional secondary hyperparathyroidism.
Primary Hyperparathyroidism
In primary hyperparathyroidism, excess production of parathyroid hormone is caused by a functional lesion in one or more of the parathyroid glands.
The normal regulatory circuits involving PTH secretion that respond to changes of the ionized calcium concentration in blood are disturbed because of uncontrolled PTH secretion from the parathyroid glands. Excess PTH secretion continues despite increased concentrations of blood calcium.
Primary hyperparathyroidism is encountered infrequently in older dogs, and it does not appear to be a sequela of renal secondary hyperparathyroidism.
PTH acts on cells of the renal tubules initially to promote the excretion of phosphorus and retention of calcium. Prolonged increased PTH secretion results in accelerated osteocytic and osteoclastic bone resorption. Mineral is removed from the skeleton and replaced by immature fibrous connective tissue.
Fibrous osteodystrophy is generalized throughout the skeleton but is accentuated in local areas, such as the cancellous bone of the skull. Increased PTH levels also inhibit renal tubular resorption of phosphorus. Because PTH stimulates osteoclast activity, resulting in a release of phosphorus from bone, the blood phosphorus concentration is only mildly decreased or even normal.
The parathyroid gland lesion that causes primary hyperparathyroidism in dogs is usually an adenoma (occasionally a carcinoma) composed of active chief cells. Typically, adenomas are single, light brown-red, and located in the cervical region near the thyroid gland.
Clinical Findings of Primary Hyperparathyroidism
In primary hyperparathyroidism, lameness follows severe osteoclastic bone resorption, and fractures of long bones occur after minor physical trauma. Compression fractures of weakened vertebral bodies can exert pressure on the spinal cord and nerves, resulting in motor and sensory dysfunction.
Facial hyperostosis with partial obliteration of the nasal cavity (by poorly mineralized woven bone and highly vascular fibrous connective tissue) and loss or loosening of teeth have been reported in dogs. As a result, affected animals might be unable to close their mouth properly and might develop gingival ulcers.
The maxillae and rami of the mandibles in animals with primary hyperparathyroidism often are coarsely thickened by the excess woven bone. Bones of the skull are markedly thinned by the increased resorption and have a characteristic “moth-eaten” appearance radiographically. In advanced cases, the mandible can be twisted gently because of loss of osteoid and severe fibrous osteodystrophy—hence the name “rubber jaw syndrome."
Congenital primary parathyroid hyperplasia has been described in German Shepherd Dog pups. The condition is associated with hypercalcemia, hypophosphatemia, increased immunoreactive PTH, and increased fractional excretion of inorganic phosphorus in the urine. Clinical signs include stunted growth, weakness, polyuria/polydipsia, and a diffuse decrease in bone density. IV infusion of calcium fails to suppress the autonomous secretion of PTH by the diffuse hyperplasia of chief cells in all parathyroid glands. The disease is inherited as an autosomal recessive defect.
Lesions of Primary Hyperparathyroidism Title
Histological demonstration of a rim of normal tissue and a partial to complete fibrous capsule in an enlarged parathyroid suggests an adenoma rather than focal hyperplasia. Chief cell carcinomas tend to be larger than adenomas and fixed to the underlying tissues because of local infiltration of neoplastic cells. In German Shepherd dogs with genetic primary hyperparathyroidism, lesions include nodular hyperplasia of thyroid C cells and widespread mineralization of the lungs, kidneys, and gastric mucosa.
Diagnosis of Primary Hyperparathyroidism
Ultrasonography to detect parathyroid gland changes
Serum biochemical testing to measure calcium and bone biomarker concentrations
Measurement of serum or plasma PTH concentration
Although other laboratory findings might vary in cases of primary hyperparathyroidism, hypercalcemia is consistent and results from accelerated release of calcium from bone.
The blood calcium concentration in healthy dogs is approximately 10 ± 1 mg/dL, depending on the animal's age and diet and on the assay method. Serum calcium values that are consistently > 12 mg/dL indicate hypercalcemia. Dogs with primary hyperparathyroidism usually have a serum calcium concentration of ≥ 12–20 mg/dL. The blood phosphorus concentration is low or in the low-normal range (≤ 4 mg/dL).
Urinary excretion of phosphorus, and often of calcium, is increased in primary hyperparathyroidism and might lead to nephrocalcinosis and urolithiasis. Accelerated bone matrix metabolism is reflected by increased urinary excretion of hydroxyproline and other bone biomarkers. Serum alkaline phosphatase activity might be increased in animals with overt bone disease.
Demonstration of increased PTH levels by a species-specific assay in an adult to aged dog with hypercalcemia, hypophosphatemia, and evidence of generalized bone disease conclusively supports a diagnosis of primary hyperparathyroidism. PTH can be measured by sensitive radioimmunoassays or immunoradiometric assays.
The intact PTH assay or dual-site assays can be performed using either serum (preferred) or plasma that has been separated and frozen (to –70°C [–94°F] in either glass or plastic tubes) as soon as possible after collection. With this method, circulating concentrations of PTH in most animals are near 20 pg/mL (in dogs, 20 ± 5 pg/mL; in cats, 17 ± 2 pg/mL), and concentrations in nonhuman primates are slightly lower (normal values also vary among laboratories).
PTH assays that use antibodies generated against the carboxy-terminal end of the human molecule usually produce less consistent results in animals.
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Differential diagnoses include the following:
other causes of hypercalcemia, such as vitamin D intoxication (overdosage)
malignant neoplasia with osseous metastasis
humoral hypercalcemia of malignancy
Hypercalcemia associated with hypervitaminosis D could be as high as in primary hyperparathyroidism; however, it is accompanied by varying degrees of hyperphosphatemia and normal serum alkaline phosphatase activity, and bone biomarkers are typically not elevated. Unlike in primary hyperparathyroidism, in hypervitaminosis D skeletal disease is usually absent, because the increased concentrations of blood calcium and phosphorus are derived principally from augmented intestinal absorption rather than from bone resorption.
Malignant neoplasia can cause moderate hypercalcemia and hypercalciuria, whereas serum phosphorus concentrations usually are normal or only slightly increased. This "hypercalcemia of malignancy" has been attributed to the synthesis of PTH-related protein (PTHrp) by many cancerous cells. PTHrp has an endocrine effect similar to that of PTH, with the exception that it lacks the stimulatory effect on vitamin D activation. The hypercalcemic effect of PTHrp is thus primarily attributable to increased osteoclastic activity rather than the enhanced intestinal absorption that would require activation of vitamin D3.
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Hypercalcemia also can be associated with multifocal osteolytic lesions associated with septic emboli, complete immobilization, osteosarcoma, hypoadrenocorticism (Addison-like disease), hypocalcitoninism due to a destructive thyroid lesion, chronic renal disease, hemoconcentration, or hyperproteinemia. Hypercalcemia is detected occasionally in dehydrated animals but usually is mild. It is attributed to fluid volume contraction that results in hyperproteinemia and increased concentrations of ionized and nonionized calcium; it resolves rapidly after fluid therapy.
Treatment of Primary Hyperparathyroidism
Ablation or surgical excision of altered gland tissue
Treatment of primary hyperparathyroidism consists of either ablation or surgical excision of abnormal parathyroid glands. Radiofrequency heat ablation can be performed when abnormal parathyroid gland tissue can be identified ultrasonographically. For this procedure, a thin catheter is advanced under ultrasonographic guidance into abnormal tissue. Radiofrequency heat is then applied to the stylet of the catheter until changes in tissue morphology become apparent ultrasonographically.
Chemical ablation is performed by advancing a thin needle into the obviously abnormal gland tissue under ultrasonographic guidance and then injecting 96% ethanol until the entire tissue appears infiltrated ultrasonographically.
For surgical excision, an attempt should be made to identify all four parathyroid glands before excising any tissue. Single or multiple adenomas should be removed in toto. If all identifiable parathyroids in the cervical region appear to be of normal or smaller size and the diagnosis is reasonably certain, surgical exploration of the thorax near the base of the heart might be necessary to localize the parathyroid tumor.
Removal or ablation of the functional parathyroid lesion results in a rapid decrease of circulating PTH concentrations, because the half-life of PTH in plasma is < 15 minutes. Because plasma calcium concentrations in animals with overt bone disease can decrease rapidly and be subnormal within 12–24 hours after surgery, they should be monitored frequently.
Postoperative hypocalcemia (≤ 6 mg/dL) can result from the following:
depressed secretory activity of chief cells resulting from suppression by chronic hypercalcemia or from injury to the remaining parathyroid tissue during surgery
abruptly decreased bone resorption resulting from decreased PTH levels
accelerated mineralization of osteoid matrix formed by hyperplastic osteoblasts (known as “hungry bone syndrome”), which was previously prevented by increased PTH levels
Infusing calcium gluconate to maintain the serum calcium concentration between 7.5 and 9 mg/dL, along with feeding high-calcium diets and providing supplemental vitamin D, corrects this serious postoperative complication.
If hypercalcemia persists for ≥ 1 week after surgery or recurs after initial improvement, a second adenoma or metastases from a carcinoma should be suspected.
Renal Secondary Hyperparathyroidism
Renal secondary hyperparathyroidism is a complication of chronic renal failure characterized by increased endogenous levels of parathyroid hormone. It is more common than primary hyperparathyroidism. Renal secondary hyperparathyroidism occurs frequently in dogs, occasionally in cats, and rarely in other species.
With progressive renal disease, serum hyperphosphatemia develops as the glomerular filtration rate decreases. Hyperphosphatemia leads to lower serum concentrations of ionized calcium because the low solubility of phosphorus in plasma results in the formation of complexes of phosphate with ionized calcium.
The concentration of activated vitamin D3 is simultaneously decreased, presumably through the effect of fibroblast growth factor 23 (FGF-23). The synthesis in bone of this phosphatonin compound is upregulated in response to hyperphosphatemia and hampers the renal activation of vitamin D3.
Decreased ionized calcium and calcitriol concentrations trigger PTH secretion by the parathyroid glands, and low concentrations of calcitriol impair the negative feedback mechanism of calcitriol on PTH secretion. As the glomerular filtration rate decreases with advancing renal disease, PTH concentrations progressively increase, leading to the clinical signs of renal secondary hyperparathyroidism.
Clinical Findings of Renal Secondary Hyperparathyroidism
The predominant clinical signs of renal insufficiency (vomiting, dehydration, polydipsia/polyuria, and depression) are usually present in cases of renal secondary hyperparathyroidism. Skeletal lesions range from minor changes with early (or mild) renal disease to severe fibrous osteodystrophy of advanced renal failure. The volume of affected bones usually is normal (isostatic), particularly in older dogs because of the slow onset of renal failure and lower metabolic activity of bones.
Hyperostotic bone lesions, such as facial swelling, can occur in younger dogs, in which the deposition of unmineralized osteoid by hyperplastic osteoblasts and production of fibrous connective tissue exceed the rate of bone resorption.
Skeletal involvement in renal secondary hyperparathyroidism is generalized but not uniform. Lesions become apparent earlier and reach a more advanced stage in certain areas, such as cancellous bones of the skull. Resorption of alveolar bone occurs early and results in loose teeth, which can be dislodged easily and interfere with mastication.
As a result of accelerated resorption of cancellous bone of the maxilla and mandible, bones become softened and pliable (“rubber jaw syndrome"), and the jaws fail to close properly, often resulting in drooling and protrusion of the tongue.
Long bones are less dramatically affected. Lameness, stiff gait, and fractures after minor trauma can result from increased bone resorption.
Lesions of Renal Secondary Hyperparathyroidism
All parathyroid glands are enlarged in renal secondary hyperparathyroidism, initially because of hypertrophy of chief cells and subsequently because of compensatory hyperplasia. PTH concentration in peripheral blood often exceeds that of primary hyperparathyroidism.
Changes such as osteoclastosis, marrow fibrosis, and a higher concentration of woven osteoid can be evident histologically. The severe hypercalcemia, hyperphosphatemia, and high PTH concentrations that occur in advanced cases of renal secondary hyperparathyroidism can cause osteosclerosis.
Diagnosis of Renal Secondary Hyperparathyroidism
Serum biochemical testing
Species-specific radioimmunoassay of serum PTH concentration
Diagnosis of renal secondary hyperparathyroidism is based on laboratory abnormalities consistent with renal insufficiency, accompanied by an increase in serum PTH concentration. Radioimmunoassay of PTH that must be species specific is commercially available for most companion animal species and horses.
Assays that measure fragments of the PTH molecule should not be used in the diagnosis of renal secondary hyperparathyroidism, because the concentration of biologically inactive PTH metabolites increases with renal failure.
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Treatment of Renal Secondary Hyperparathyroidism
Phosphorus-restricted diets
Oral phosphate binders
Oral calcitriol supplementation
Treatment options for renal secondary hyperparathyroidism include dietary modification, administration of calcitriol (the bioactive metabolite of vitamin D3) in combination with oral supplementation of phosphate binders, and management of underlying renal disease.
Prescription diets with restricted dietary phosphorus are available. Oral calcitriol (1.5–3.5 ng/kg every 24 hours) has reversed hyperparathyroidism due to chronic renal failure (1); however, calcitriol therapy is contraindicated with hyperphosphatemia or hypercalcemia because it increases intestinal resorption of both minerals, worsening the potential for calcium phosphate deposition in soft tissues and blood vessels. (Special compounding of calcitriol is needed, because the dosages currently available commercially are much larger than those needed clinically.)
Dietary phosphorus binders are used to decrease the amount of phosphorus available for absorption in the intestines and should be administered with meals. This therapy is especially important during calcitriol supplementation, because calcitriol increases the absorption of phosphorus and calcium.
Prognosis of Renal Secondary Hyperparathyroidism
If untreated, renal secondary hyperparathyroidism results in irreversible hypertrophy of the parathyroid glands, a condition also known as tertiary hyperparathyroidism. In this stage, hyperparathyroidism becomes unresponsive to treatment and requires surgical removal of the hypertrophic parathyroid glands.
Nutritional Secondary Hyperparathyroidism
Nutritional secondary hyperparathyroidism is the result of a persistent imbalance of the dietary calcium and phosphorus supply. Persistent deficiencies of dietary calcium and/or excessive supply of phosphorus can result in decreased plasma calcium and increased plasma phosphorus concentrations that trigger increased secretion of parathyroid hormone and hyperplasia of the parathyroid glands.
Vitamin D deficiency can also cause plasma calcium concentrations and, to a certain degree, plasma phosphorus concentrations to decline, thereby also inducing increased PTH secretion. Hypovitaminosis D, however, is not necessarily caused by insufficient dietary supply. In many instances, the underlying cause of hypovitaminosis D is impaired conversion of calcidiol, the inactive form of vitamin D3.
Activation of vitamin D3 is hampered with excessive dietary phosphorus content (an effect of increased secretion of FGF-23) or with chronic renal disease (renal secondary hyperparathyroidism). The ensuing hyperparathyroidism restores normal blood calcium concentrations by stimulating mobilization of calcium from bone and increased excretion of renal phosphorus. Persistent demineralization of bone leads to fibrous osteodystrophy.
Nutritional secondary hyperparathyroidism has been described in several animal species; however, it is most prevalent in equids. Horses that are fed diets with inadequate calcium or excessive phosphorus, or with a calcium:phosphorus ratio of ≤ 1:3, are prone to develop the condition (2).
Consumption of large amounts of oxalate-rich plants can also cause nutritional secondary hyperparathyroidism. Oxalates bind dietary calcium, thereby decreasing its availability. Affected horses develop fibrous osteodystrophy (see Osteomalacia). Puppies of large dog breeds are susceptible because of their calcium requirements, particularly when fed a raw meat, boneless diet.
Clinical Findings of Nutritional Secondary Hyperparathyroidism
Clinical signs observed with nutritional secondary hyperparathyroidism are related primarily to ongoing bone demineralization. Bone deformities and epiphysitis occur particularly in young and growing animals. Affected animals might show pain, unthriftiness, reluctance to walk, or intermittent or shifting lameness. Deformation of the skull, with symmetrical swelling of facial bone, is well recognized in horses. The involvement of teeth can result in masticatory problems, anorexia, and loss of body condition.
Neurological signs such as pain, ataxia, or paresis have been associated with vertebral fractures with ensuing spinal cord trauma, or compression of nervous tissue by bone swelling. Nutritional secondary hyperparathyroidism that is associated with acute hypocalcemia can lead to increased nerve excitability with muscle twitching or tetany.
Diagnosis of Nutritional Secondary Hyperparathyroidism
Dietary analysis
Elevated PTH concentration
Urinary fractional excretion of calcium and phosphorus
Results of blood biochemical analysis might vary in cases of nutritional secondary hyperparathyroidism. The most consistent findings are mildly to moderately elevated blood phosphorus concentrations, with a markedly elevated PTH concentration. Blood calcium levels might be decreased or within the normal range because of increased bone breakdown.
The activity of alkaline phosphatase and other bone biomarkers is usually increased. Urinalysis reveals decreased fractional excretion of calcium and markedly increased fractional excretion of phosphorus.
Whenever possible, the diet should be evaluated for calcium, phosphorus, and vitamin D content, as well as for the presence of calcium-binding compounds such as oxalates or zeolites.
Treatment of Nutritional Secondary Hyperparathyroidism
Dietary correction
Calcium supplementation
Treatment of nutritional secondary hyperparathyroidism consists of adjusting the dietary content of calcium, phosphorus, and vitamin D to current recommendations for the particular species and age group. Calcium can be supplemented in the diet as ground limestone.
Access of horses to plants containing large quantities of oxalates should be restricted.
The use of NSAIDs is advisable to control pain.
Prognosis of Nutritional Secondary Hyperparathyroidism
Full recovery from nutritional secondary hyperparathyroidism is possible; however, at advanced stages of the disease recovery could take several months, and bone deformities might not resolve entirely. Complete recovery is also unlikely with nerve or spinal cord trauma caused by healed vertebral fractures.
Key Points
Fibrous osteodystrophy is a chronic disease of bone resulting from excessive synthesis of parathyroid hormone.
The most common etiologies of excessive PTH secretion are primary hyperparathyroidism (attributable to dysfunction of the parathyroid glands), chronic renal disease leading to renal secondary hyperparathyroidism, and nutritional secondary hyperparathyroidism.
Fibrous osteodystrophy is characterized by bone demineralization associated with fibrous swelling, deformities, and fractures of bones.
For More Information
Toribio RE. Disorders of calcium and phosphate metabolism in horses. Vet Clin North Am Equine Pract. 2011;27(1):129-147.
Also see pet owner content regarding disorders associated with calcium, phosphorus, and vitamin D in dogs and cats.
References
Zafalon RVA, Ruberti B, Rentas MF, et al. The role of vitamin D in small animal bone metabolism. Metabolites. 2020;10(12):496. doi:10.3390/metabo10120496
Toribio RE. Disorders of calcium and phosphate metabolism in horses. Vet Clin North Am Equine Pract. 2011;27(1):129-147. doi:10.1016/j.cveq.2010.12.010
