Unusual Case of Osteopenia Associated With Nutritional Calcium and Vitamin D Deficiency in an Adult Dog

Introduction

Rubber jaw syndrome is described as a group of lesions characterized by loss of the lamina dura of the teeth, loose teeth, and osteopenia of the bones of the skull.^1–4 In dogs, this syndrome occurs secondary to renal hyperparathyroidism and, rarely, from primary hyperparathyroidism.^1–5 Both conditions are characterized by an increase of plasma parathormone concentration and variable alteration of metabolism of vitamin D.⁶ Radiographic features of these lesions are well described in the dog.^1–3 Computed tomography (CT) has never been used to evaluate skull osteopenia, but it is potentially useful because of two distinct advantages over conventional radiographic techniques. The first advantage is the elimination of superimposition of structures, and the second is the ability to precisely measure bone mineral density because of the enhanced contrast between structures.^7–9

The purpose of this report is to describe an unusual cause of rubber jaw syndrome in the dog—namely, hyperparathyroidism secondary to nutritional calcium and vitamin D deficiency. The clinical findings are described, and the results of parathormone and vitamin D assays and tomodensitometric studies are provided.

Case Report

A 6-year-old, spayed female rottweiler, housed primarily outdoors and weighing 35 kg, was presented with facial enlargement that had begun 1 month previously. The dog had recently developed difficulty eating. She had been fed a homemade diet throughout the preceding year, because of the diagnosis of lymphocytic-plasmacytic enterocolitis with lymphangiectasia and villous atrophy 18 months earlier. The diet consisted of 75 g of an inexpensive meat for animals (considered as a 20% fat beef, fed raw), 500 g (uncooked weight) pasta (about 1500 g once cooked) that was boiled, and 250 g of canned green beans [Table 1, Diet A]. The nutritional composition of this diet was calculated using composition tables.¹⁰ No vitamin or mineral supplements were provided.

Physical examination showed that the dog was in good condition but had marked, diffuse swelling of both jaws. Palpation revealed nonpainful swelling of the maxilla and mandible bilaterally [Figure 1]. The jaws were flexible, and the teeth moved with digital pressure. Radiographic and tomodensitometric^a examinations of the skull were performed [Figures 2, 3A, 3B]. Both revealed severe osteopenia of the skull bones. Computed tomographic images showed diffuse bone resorption of the skull, with loss of almost all maxillary, zygomatic, and mandibular cortical and trabecular bone density. Thinning of the incisive, frontal, temporal, and parietal cortical bones was also seen. The disappearance of the lamina dura made the teeth appear to float in soft tissue [Figures 3A, 3B] rather than remain embedded in alveolar bone [Figures 4A, 4B]. Tomodensitometric examination of the axial and appendicular skeleton was unremarkable, and cortical bone opacity was normal.

The generalized, severe osteopenia of the skull in this dog was suggestive of metabolic bone disease and of hyperparathyroidism in particular. Differential diagnosis was primary hyperparathyroidism or secondary hyperparathyroidism associated with renal disease or calcium deficiency (with or without vitamin D deficiency) and vitamin D malabsorption. Initial results of a biochemical profile and urinalysis were unremarkable, except for low blood urea nitrogen [Table 2]. Frozen plasma and serum, collected in ethylenediaminetetraacetic acid (EDTA) and stored in light-proof containers, were sent as described elsewhere to an independent animal health diagnostic laboratory for intact parathormone (PTH) determination (by means of a two-site immunoradiometric assay^b previously validated for dogs) and for determination of vitamin D concentration (by means of a standardized radioimmunoassay).^c,d,11–15 The plasma PTH concentration was markedly elevated (104.6 pmol/L; reference range 2 to 13 pmol/L). The serum concentration of 25-hydroxycholecalciferol (25-OHD₃) was very low (<0.7 nmol/L; reference range 19 to 90 nmol/L), whereas the serum concentration of calcitriol (1,25-OHD₃) was within the reference range (43.2 pmol/L; reference range 31 to 149 pmol/L).

Normal values for calcium, phosphorus, and calcitriol suggested that primary hyperparathyroidism was unlikely and provided evidence for secondary hyperparathyroidism. The good body condition of the dog and the results of the urine analysis and serum creatinine assay ruled out the possibility of hyperparathyroidism secondary to renal failure. Based on the history of the dog being fed a diet low in good-quality proteins, calcium, and vitamin D, a nutritional calcium and vitamin D deficiency associated with secondary hyperparathyroidism was diagnosed.

Treatment of the dog consisted exclusively of dietary modifications. Twice-daily feedings of a nutritionally complete and balanced homemade diet, providing almost the same amount of energy, was started. This new diet included 500 g of beef (fed raw) with 15% fat, 250 g of canned green beans, 167 g of uncooked pasta (about 500 g once cooked), 12 g of raw rapeseed oil, and 20 g of Pet Phos Ca/P=2.^e The Pet Phos Ca/P=2 is a vitamin-mineral premix formulated for adult dogs and has a calcium to phosphorus ratio of 2:1 based on wet weight. It provided 400 IU of vitamin D₃ [Table 1, Diet B]. The diet contained nutritionally adequate, but not excessive, amounts of calcium and vitamin D (i.e., the minimal recommendation of 0.6% calcium [dry matter], a calcium to phosphorous ratio of 1:2, and 500 IU of vitamin D per kg of dry matter, based on advice from the Association of American Feed Control Officials).¹⁶

The dog was reexamined 2 weeks later. The dog no longer had difficulty eating, and mobility of the teeth was dramatically reduced. At a recheck examination 4 months later, palpation of the jaws revealed marked, firm swelling. Tomodensitometric examination showed pronounced enlargement of the maxilla and mandible, associated with heterogeneous mineralization of the bones. The bone density of the skull had increased [Figures 5A, 5B]. Plasma PTH concentration had decreased (20.4 pmol/L), serum 25-OHD₃ concentration had normalized (84 nmol/L), and serum calcitriol concentration had increased (168 pmol/L). The dog’s body weight was 40 kg, which represented a 14% weight gain. The diet was then modified to provide a daily energy intake estimated to be adequate for a 35-kg spayed dog (i.e., 156 kcal metabolizable energy for maintenance × body weight^0.67 × 0.8 for a low activity, leading to 1350 kcal metabolizable energy per day).^17,18 The new diet consisted of 100 g of beef (fed raw) with 5% fat, 300 g of beef (fed raw) with 15% fat, 400 g of canned green beans, 100 g of uncooked pasta (about 300 g once cooked), 8 g of rape-seed oil, and 20 g Pet Phos Ca/P=2 [Table 1, Diet C].

At the time of manuscript preparation (2.5 years after presentation), the dog is still alive. Its jaws are firm upon palpation, but they are thinner when compared to previous examinations. Computed tomography scans done recently show continued mineralization and architectural reorganization of the skull bones [Figures 6A, 6B]. Plasma PTH (3.8 pmol/L), serum 25-OHD₃ (63 nmol/L), and serum calcitriol concentrations (96 pmol/L) are all within reference ranges.

Discussion

The metabolic osteopathy in the dog of this report was evaluated by multiple imaging procedures and hormone measurements. The reference ranges for calcitriol and PTH used for this clinical case were consistent with those in other published reports.^13,19 However, the reference range for 25-OHD₃ was lower than two reference ranges previously published using a different methodology (i.e., a competitive binding assay).^20,21 In humans, these different 25-OHD₃ assays have caused discrepancies between laboratories, so each laboratory must generate its own reference values.^22–24

In the present case, a combined deficiency of vitamin D and calcium was diagnosed, rather than an isolated vitamin D or calcium deficiency. A diet with an isolated deficiency in calcium would also have led to secondary hyperparathyroidism, as observed in dogs fed a low-calcium diet for long periods. In these conditions, an increase in the circulating concentration of PTH is considered an appropriate physiological response to maintain calcium concentrations in plasma and interstitial fluid compatible with life. This response is mediated through a direct effect of PTH on bone and renal calcium resorption, as well as through the activation of vitamin D.²⁵ Parathormone stimulates the renal conversion of 25-OHD₃ (the storage form of vitamin D) to calcitriol (the active vitamin D metabolite), which then stimulates the active absorption of calcium in the intestine.²⁶ Therefore, in the absence of a concomitant vitamin D deficiency, the increased PTH would have been associated with a low to moderate increase in 25-OHD₃ concentration and a significant increase in calcitriol concentration.²⁷

In the dog reported here, vitamin D deficiency was diagnosed on the basis of dietary analysis and low plasma 25-OHD₃ concentration, despite plasma calcitriol and serum calcium being normal. In humans, 25-OHD₃ has been considered the parameter of choice for assessing vitamin D status.²⁸ The measurement of 25-OHD₃ is preferred to that of calcitriol for the diagnosis of vitamin D deficiency, because serum calcitriol levels have been reported to remain within the normal range for long periods of time in several studies of human osteomalacia.^29,30 Low to normal concentrations of calcitriol have also been reported in experimental dogs fed a diet deficient in vitamin D.²⁷ As plasma calcitriol concentration was normal in the current case, a diagnosis of isolated vitamin D deficiency was not considered, because 25-OHD₃ has no significant direct effect on the parathyroid gland.²⁵

A deficiency in oral calcium intake remained the most probable explanation for the large elevation in plasma PTH in this dog. Results of the biochemical analyses and the hormonal profile of this dog (i.e., high PTH, low 25-OHD₃, normal calcitriol levels, and normal calcium concentrations) had combined features associated with calcium and vitamin D deficiency and were consistent with previously obtained data from adult dogs experimentally fed a low-calcium/low-vitamin D diet for a similar length of time.³¹

The clinical presentation of diet-induced osteomalacia was unusual in this dog. Very few reports have documented spontaneous diet-induced osteopathies in dogs.^32–36 No exhaustive descriptions of the imaging and hormonal characteristics of clinically detectable osteomalacia in adult dogs or of nutritional osteomalacia with swelling of the jaws have been published. Modifications to the skeleton of young, developing animals that arise with vitamin D or calcium deficiency are well known. These deficiencies lead to bony features that are typical of rickets (e.g., physis irregularity, enlargement of metaphyses, long bone deformities secondary to defective mineralization, and cartilaginous changes in the growth plate) and/or severe osteopenia involving predominantly the limbs and spine.^27,37–39 The bony lesions described in this report could be attributed to osteomalacia, which may be a better term than rickets to apply to cases of diet-induced osteopathy in adults.⁴⁰ In contrast to what has been reported for young dogs with rickets, the skull changes seen in this dog were not associated with visible limb or spinal alterations.

Spontaneous rickets and osteomalacia have been described in other species (i.e., cat, skunk, wild animals), but preferential involvement of the skull has not been reported.^41–45 Nutritional osteomalacia in horses is characterized by fibrous osteodystrophy of the skull that results in radiographic osteopenia.³⁸ The disorder is known as bran disease, miller’s disease, bighead disease, or nutritional secondary hyperparathyroidism, and its clinical presentation is very similar to that described for the dog in this study.³⁸ In horses, this disorder most often occurs in the young, and it may be caused by a diet that is low in calcium, high in phosphorus, or both.^46,47 Vitamin D deficiency is thought to be a potential cofactor, but its involvement has not been definitively demonstrated in horses.^46,47 Horses are unusual in that their plasma concentration of 25-OHD₃ is about one-tenth the plasma concentration of other species, and vitamin D deficiency is well tolerated.^46,47

The clinical presentation of this dog was similar to the lesions grouped as rubber jaw syndrome, a condition that has been observed in a small number of dogs secondary to renal hyperparathyroidism and, rarely, primary hyperparathyroidism.^1–5 Imaging data showed loss of the lamina dura of the teeth and a decrease in the opacity of all bones of the skull, which were considered characteristic of this syndrome.⁴⁸ Renal secondary hyperparathyroidism causes extensive bone resorption and fibroosseous tissue formation that predominate in the skull. In this case, a link between rubber jaw syndrome and renal insufficiency was ruled out based on clinical and biological investigations. Instead, the estimated food intake of the dog confirmed calcium and vitamin D deficiency.

The history of lymphocytic-plasmacytic enteritis with lymphangiectasia may have contributed to a vitamin D malabsorption, although objective assessments of bowel histopathology and physiology were not performed. A decrease in plasma vitamin D₃ concentration has been identified in two Yorkshire terriers with protein-losing enteropathy and similar intestinal lesions.⁴⁹ Laboratory anomalies (i.e., high plasma PTH and low serum vitamin D concentrations) consistent with the case reported here have also been recently reported in two other dogs with protein-losing enteropathies.⁵⁰ In both reports, a suspected calcium malabsorption (independent of vitamin D malabsorption) was considered but not explored. In the case reported here, standard equilibration of the diet led to a rapid clinical improvement and normalization of the 25-OHD₃ concentration. Nevertheless, the PTH concentration remained slightly elevated 4 months later. These results were consistent with minor changes in calcium absorption and with findings obtained in a model of high-turnover osteopenia induced by gastrectomy in pigs.⁵¹ In these pigs and in dogs experimentally fed a low-calcium diet, increased PTH concentrations were associated with an increase in calcitriol concentrations, similar to that seen in the present study.^27,51 Despite this evidence for a mild dietary calcium deficiency, over-supplementation was not considered. The reason was twofold: it might have led to osteopathies, and reossification of the skull bones was demonstrated objectively.

It was not clear why the dog reported here developed this particular pattern of bony lesions. The widespread use of commercially formulated food has decreased the frequency of nutritional bone disease, and experimentally-induced nutritional bone disease in dogs has not usually been associated with such dramatic involvement of the skull.^27,52–56 Some of the experimental studies were carried out in young dogs, and the age at which the deficient diet was introduced in the present case may have played a role in the development of the syndrome. Renal rubber jaw syndrome has been described, however, in young dogs with renal dysplasia, in old dogs with chronic renal failure, and in both young and old horses with bighead disease. The respective roles of calcium deficiency and vitamin D deficiency in the development of this unusual clinical expression of nutritional bone disease in dogs also remain to be determined.

Imaging techniques, such as radiography and CT, provided valuable information on the dog presented in this report; CT identified both the initial bony lesions, and it accurately visualized new mineralization. Historically, primary or secondary hyperparathyroidism was diagnosed purely on the basis of clinical signs or abnormalities in serum calcium or phosphorous concentrations. As these changes occur late in the clinical course of these diseases, the development of standard radiographic techniques and the validation of PTH and vitamin D assays have made it possible to detect these conditions earlier and more accurately.²⁸ Because subtle changes can be detected earlier on CT scans than with standard radiography, the application of CT in the diagnosis of dogs with metabolic bone disease and no obvious clinical abnormalities remains to be determined.⁵⁷

Conclusion

An adult dog was diagnosed with a nutritional calcium and vitamin D deficiency associated with secondary hyperparathyroidism that caused clinical signs of rubber jaw syndrome. Thus, spontaneous hyperparathyroidism secondary to nutritional calcium and vitamin D deficiency should be considered as a differential diagnosis in adult dogs with rubber jaw syndrome. Plasma PTH, serum 25-OHD₃, and serum calcitriol concentrations aided in the diagnosis. Tomodensitometry was useful for accurately evaluating the skull lesions and for evaluating improved mineralization after treatment.