SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Physiology Of Calcium And Phosphorus Metabolism
  5. Dental Disease
  6. Acknowledgement
  7. References

Dental disease is considered as one of the, if not, the most common disorders seen in pet rabbits. This article provides a review of the scientific literature and an overview of the peculiarities of calcium homeostasis in the rabbit in an attempt to draw together current thinking on the cause of dental disease. A complete understanding of the aetiology and pathophysiology of rabbit dental disease is necessary for the veterinary practitioner to establish a proper therapeutic plan, prognosis and ultimately prevention of this common cause of morbidity and mortality in pet rabbits.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Physiology Of Calcium And Phosphorus Metabolism
  5. Dental Disease
  6. Acknowledgement
  7. References

Oral cavity diseases are the most frequently reported disorders in small herbivorous mammals (Wiggs & Lobprise 1997a, Verstraete & Osofsky 2005). In rabbits, guinea pigs, chinchillas and degus, a wide range of local and systemic conditions which affect the mouth and oral cavity have been implicated including hereditary, infectious, metabolic, traumatic (foreign bodies included) and neoplastic disorders and additionally lack of chewing and poor dietary abrasive properties (Lindsey & Fox 1994, Harcourt-Brown 2002, Crossley 2003a).

Different forms of congenital, developmental or acquired dental disease are clinically manifested by hypersalivation, anorexia, chewing disturbances, change of feed component preferences and poor body condition. Dental disease can also be accompanied by the development of facial abscesses, moist dermatitis, epiphora, exophthalmia and damage of the temporomandibular joint. Factors that affect tooth positioning such as abnormalities of jaw width, length and height may also result in malocclusion, as may variations in tooth arrangement along the jaw, the degree of eruption, tooth rotation and tipping (Crossley 2003b).

Many clinical articles have been published regarding the diagnosis and clinical treatment of dental disease in rabbits. However, specific scientific information concerning the aetiology of dental disease remains scarce.

Physiology Of Calcium And Phosphorus Metabolism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Physiology Of Calcium And Phosphorus Metabolism
  5. Dental Disease
  6. Acknowledgement
  7. References

Calcium and phosphorus absorption and excretion in rabbits

In most mammalian species, calcium is absorbed from the adult gastrointestinal tract by an active transport system in the brush border of enterocytes that involves calcium-dependent ATPase, regulated by the active form of vitamin D3. Calcium is moved from the intestinal lumen to the circulation by a paracellular process, i.e. down a chemical gradient through the enterocyte junctions in newborns and young animals (Bronner 1998, Tryfonidou et al. 2002, Bass & Chan 2006). In contrast, in both young and adult rabbits, almost all the available calcium is absorbed from the diet (independent of vitamin D3) by passive diffusion through the intestine wall (Buss & Bourdeau 1984, Kamphues et al. 1986, Barr et al. 1991). Only when dietary calcium is low, do rabbits use active calcium transport.

Factors which decrease intestinal absorption of calcium include pH of ingesta, presence of calcium ion binders (phytates, phosphate and oxalates), glucocorticoids and fat (Harcourt-Brown 2002, Marounek et al. 2009). Factors which facilitate calcium absorption include the presence of bile salts and lactose. In rabbits, increasing dietary phosphorus content (from 0·1 to 0·8%) at a constant calcium concentration (0·5%) results in a dramatic decrease in calcium excretion through the kidney and increased faecal calcium output because of the formation of CaPO4 complexes (Ritskes-Hoitinga et al. 2004). With excessively high-dietary calcium intake, intestinal absorption in rabbits is not reduced (as in other mammals) but calcium renal excretion is increased (Whiting & Quamme 1984).

Phosphorus is primarily absorbed in the small intestine via an active transport process, controlled by the active form of vitamin D3. A major factor influencing phosphorus availability from plant materials in non-ruminant animals is the presence of phytates and phytases (Mateos et al. 2010). Phytates are phosphorus-rich complexes that are not degraded by endogenous enzymes. In the rabbit, phytate phosphorus is well utilised because of phytase production by the microorganisms of the caecum (Marounek et al. 2009). Most of the phosphorus is recycled through soft faeces followed by coprophagy and, therefore, should result in an almost complete utilisation of phytate phosphorus (Mateos et al. 2010). In addition, natural phytases present in wheat and other ingredients, as well as in other exogenous sources, may facilitate phytate hydrolysis and absorption of phosphorus in the upper part of the digestive tract (Marounek et al. 2003).

In rabbits, increased dietary phosphorus intake causes increased urinary and faecal phosphorus excretion (Ritskes-Hoitinga et al. 2004).

The role of parathyroid hormone and vitamin D in rabbits

The metabolism of calcium and phosphate ions are closely related. The two most important hormones responsible for regulating the extracellular concentration of these ions are parathyroid hormone (PTH) and the active form of vitamin D3 (also known as calcitriol; 1,25-dihydroxyvitamin D3; [1,25-(OH)2D]; or 1,25-dihydroxycholecalciferol). The secretion of PTH is rigidly controlled by the extracellular concentration of calcium ions. PTH is responsible for the fine regulation of the serum calcium concentration on a minute-to-minute basis, by virtue of its effects on calcium mobilisation from bone and the rate of calcium (and phosphate) excretion into the urine.

Calcitriol is primarily responsible for regulating the quantity of calcium absorbed in the small intestine, and it also participates with PTH in the regulation of mineral mobilisation from bone. The effect of increased calcitriol requires hours rather than minutes, so that it may be more important in the long-term maintenance of calcium balance rather than the minute-to-minute regulation of the serum concentration of calcium ions.

The term vitamin D is used to refer to a group of closely related sterols. In the liver, cholecalciferol is converted to 25-hydroxycholecalciferol (calcidiol), which is further converted in the cells of proximal tubules of the kidney to the more active metabolite 1,25-dihydroxycholecalciferol (calcitriol). Calcitriol is also produced in placenta and in macrophages.

One of the primary roles of vitamin D is the regulation of calcium and phosphorus absorption and metabolism for bone health. This role is especially important during pregnancy and lactation because bones develop rapidly during this period. Vitamin D3 levels are very important for maintaining bone mineral density.

However, the best indicator of overall vitamin D status is the circulating concentration of 25-hydroxycholecalciferol, because it is the body's main storage form of vitamin D (Holick 2003).

In large herbivores (cattle, sheep, horses) and omnivores (rats, pigs, human), the biosynthesis of vitamin D3 from 7-dehydrocholesterol (ergosterol) occurs in the skin exposed to ultraviolet light (How et al. 1994, Holick 2003) and it is thought that this process also occurs in rabbits. A preliminary study of Fairham & Harcourt-Brown (1999) recommended exposing rabbits to natural daylight, however, there are no further scientific data to support this recommendation. However, clients should be encouraged to expose rabbits to natural conditions, as it supports normal behaviour and normal grazing.

Nutritional requirements

The optimal dietary calcium content for growing and adult rabbits was suggested by Lowe (1998) to be 0·5 to 1%. This is in agreement with a later study using dexa scanning (for bone density analysis) that found 0·6 to 1% was required for optimal bone density (Norris et al. (2001). Further, the calcium to phosphorus dietary ratio should be at least 1-2:1 to achieve normal homeostatic balance (Harris 1994).

The minimum dietary phosphorus content has been quoted as 0·22% to 0·3-0·7% (Mathieu & Smith 1961, Mateos & de Blas 1998). However, a more recent experimental study by Ritskes-Hoitinga et al. (2004) showed that even a dietary phosphorus content as low as 0·2% with 0·5% calcium could cause some degree of kidney calcification. However, in clinical practice, it is hard to achieve such a low-phosphorus diet based on natural ingredients and optimal fibre content, and optimal dietary phosphorus recommendations should more practically be in the range of 0·3 to 0·4%.

The optimal dietary vitamin D content for rabbits was reported by Lowe (1998) as 800 to 1200 IU/kg. However, feeding rabbits even with 1000 IU/kg vitamin D can result in soft tissue calcification (Kamphues et al. 1986) and so extreme caution in using supplements for rabbits is required.

Physiological plasma/serum levels of calcium in rabbits

In contrast to other mammalian species, as a result of vitamin D-independent intestinal calcium absorption, the total circulating calcium concentrations fluctuate widely, i.e. if the dietary calcium intake is high, the total calcium concentration is also high (Brommage et al. 1988). Therefore, rabbits have relatively high concentrations of total calcium in plasma but the ionised fraction is more consistent and similar to other mammals (McLean & Hastins 1935, Norris et al. 2001). Circulating ionised calcium concentrations generally range between 1·67 and 1·76 mmol/L (Warren et al. 1989, Bas et al. 2004). It is therefore important to differentiate between total and ionised calcium when discussing calcium in rabbits.

Various authors describe different and wide physiological reference intervals for total circulating calcium or phosphorus concentrations (Table 1). When fed a high-calcium diet, adult rabbit serum calcium concentrations could increase rapidly above 4·5 mmol/L because of passive calcium intestinal absorption (Kamphues et al. 1986). However, higher calcium concentrations may also indicate undiagnosed renal failure or reduced glomerular filtration rates. Although the circulating calcium concentration in rabbits is higher than in most mammals, PTH values are comparable (Norris et al. 2001). However, unlike other mammalian species, the changes in PTH in rabbits occur at relatively high concentrations of calcium, suggesting that the parathyroid gland of the rabbit is set to respond to changes in ionised calcium within its own physiological range (Warren et al. 1989). Normal circulating values for calcium, phosphorus, PTH and vitamin D are given in a Table 1.

Table 1. The reference plasma/serum concentrations for selected plasma/serum parameters
ParameterPublished wide reference intervalsReference concentrations suggested by authors (VJ, SR)
  1. a

    Buss & Bourdeau 1984, Goad et al. 1989, Warren et al. 1989, Gillet 1994

  2. b

    Hewitt et al. 1989, Gillet 1994, Jenkins 2008 Warren et al. 1989, Harcourt-Brown & Baker 2001, Bas et al. 2004, 2005

  3. c

    Eckermann-Ross 2008

Total calcium1·49 to 3·7 mmol/La2·1 to 3·5 mmol/L
Phosphorus0·88 to 2·35 mmol/Lb1·0 to 1·5 mmol/L
Basal parathyroid hormone23·7 to 113·0 pg/mL
1,25 dihydroxycholecalciferol (calcitriol)52 to 68 pg/mLc
25-hydroxycholecalciferol30 to 38 ng/mLc

Dental Disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Physiology Of Calcium And Phosphorus Metabolism
  5. Dental Disease
  6. Acknowledgement
  7. References

Dental disease is widely reported to be one of the most common diseases of pet rabbits (Harcourt-Brown 2007b, Jekl et al. 2008, Capello & Lennox 2011). Despite its prevalence in pet rabbits, dental disease is infrequently reported in laboratory rabbits. The frequent association of dental disease with an inappropriate diet (resulting in lack of wear) in pet rabbits appears to conflict with the lack of dental disease documented in laboratory rabbits fed only liquid food (Latour et al. 1998). However, any conclusions associated with the impact of liquid food on dentition may be misleading as specific examination of the oral cavity was not reported in the latter study. More recently, Okuda et al. (2007) reported a high prevalence of dental disease (100% of the 42 rabbits studied) in laboratory rabbits.

In rabbits suffering from dental disease, the pathophysiological relationship among orthodontic, periodontal and endodontic lesions is unclear (Verstraete & Osofsky 2005) and appears to be much more complex than in other mammals. Most likely, multiple factors are involved in the development of a syndrome of acquired dental disease such as traumatic injuries of the orofacial area, less abrasive diet, reduced chewing movements, altered chewing actions, changes in the structure and adaptability of the chewing muscles, temporomandibular joint disorders, inappropriate dietary phosphorus, inappropriate dietary calcium, malabsorption and systemic disease (Poikela et al. 2000, Harcourt-Brown 2002, Crossley & Aiken 2003, Fujisawa et al. 2003, Langenbach et al. 2003, Crossley 2005, Harcourt-Brown 2007a,2007b, Wolf & Kamphues 2009).

In pet rabbits, the most common aetiological theories for dental disease are genetic/inheritance factors, trauma, iatrogenic malocclusion, lack of abrasive food that leads to insufficient or abnormal dental wear (Crossley 1995) and underlying metabolic disease because of calcium and vitamin D deficiency (Harcourt-Brown 2007a).

Genetic/inheritance factors

Mandibular prognathism

Mandibular prognathism is inherited as an autosomal recessive (mp/mp) trait with incomplete penetrance (81%). Affected animals have reduced skull and maxillary diastema length, without significant deviation from the normal length of mandibles. Hereditary mandibular prognathism (brachygnatia superior, hypognatia) that leads to incisor malocclusion has been well described (Lindsey & Fox 1994). In affected rabbits, malocclusion of incisors usually first appears after the third week of life. Initially, there is an edge to edge bite with blunting of incisival cutting edges. Later, positioning of the lower incisor anterior to the uppers occurs (Fig 1). However, there have been no recent genetic studies in pet dwarf rabbit breeds to investigate the effect of this gene on dental disease development. There are also no differences between the prevalence of dental disease in dwarf and other rabbit breeds according to Harcourt-Brown (2006).

image

Figure 1. (A) Obvious acquired incisor malocclusion in a three-year old intact male rabbit. Incisor malocclusion is mostly secondary to cheek teeth crown elongation and care should be taken to diagnose inherited disease before radiography and thorough history are taken. (B) Congenital incisor malocclusion in a two-month old rabbit with mandibular prognatism

Download figure to PowerPoint

Hypodontia

The most commonly seen hypodontia in rabbits appears to be caused by the absence of peg teeth (dentes incisivi minores), which could occur in all breeds. Sometimes, a reduced number of maxillary premolars are also seen. Neither of these congenital abnormalities is associated with dental disease development.

Other inherited diseases

Other diseases which affect the rabbit skull and dentition have been described; however, they are extremely rare, e.g. achondroplasia and osteopetrosis. Features of osteopetrosis include skeletal sclerosis together with hypocalcaemia, hypophosphataemia and osteoclasts of reduced numbers and abnormal cytology. The chief attributes of the osteopetrosis are incisor tooth abnormalities with an initial subnormal development and subsequent retarded and abnormal growth. The most frequently observed condition at birth is the absence of, or the rudimentary state of one or more of the teeth. The enamel of these abnormal teeth is often an opaque dirty grey colour or a dull yellowish white. The molar teeth are similarly affected. The commercial available mutants are used as an animal model for this disease (Pearce & Brown 1948).

Traumatic injuries

Traumatic incisor, premolar or molar fracture may all occur as a consequence of falling from a height or gnawing/chewing on hard substances. Jaw or other skull bone fractures may also lead to incisor or premolar and molar malocclusion and subsequent elongation.

Iatrogenic malocclusion

Iatrogenic tooth injuries are usually the result of improper clipping of teeth. Even though this technique should now be considered an improper veterinary procedure, it is still commonly performed in some veterinary practices. In referred cases, the author (VJ) sees that more than 10% of rabbits have had their incisors shortened with pliers, pincers, bone cutters, nail trimmers, cheek teeth molar cutters or scissors, which has resulted in more pronounced incisor malocclusion (unpublished data). Incisor shortening by this way results in complete incisor fracture, taking the tooth out of normal occlusion or, at best, causing partial enamel fractures at the place of clipping. In addition, enormous pathological forces on the tooth during tooth crown shortening could cause periodontal damage, alveolar bleeding, tooth torsion and clinical root fractures and pathologies (Jekl et al. 2008, Fig 3). Iatrogenic pulp exposure is also very common when adjusting the size of elongated incisor teeth, particularly when this is repeated; as the tooth shortening often permits the teeth to erupt faster with the result that the pulp cavities become longer (Crossley 2005).

Facial abscesses can also be the result of improper incisor shortening (Minarikova et al. 2012). Osteomyelitis associated with improper incisor correction occurs in 8% of rabbits with odontogenic abscesses in the author's (VJ) practice (unpublished data). As a consequence, shortening incisors with the instruments listed above should never be performed, (Crossley 2003a, Jekl et al. 2008, Capello & Lennox 2012).

Lack of tooth abrasion; the ‘lack of chewing’ theory

Diets provided to captive rabbits rarely match those eaten in the wild, as they are generally higher in energy and nutrient content, lower in fibre, possess less abrasive properties (Wolf & Kamphues 1996) and are often pre-processed into unnatural forms (Crossley 2005). The general result is a threefold reduction in duration of chewing (Wolf et al. 1997, & 1999, Crossley 2005). This leads to reduced tooth wear from reduced tooth on tooth contact during chewing, abnormal chewing patterns used when feeding on unnatural foods (decrease in lateral masticatory action) and albeit less importantly lack of naturally abrasive food content. Furthermore, when all factors are taken together there is often a 16-fold reduction in cheek tooth wear rate (Crossley 2005).

Crossley (1995) described that this lack of tooth wear resulted an continued eruption and abnormal incisor and cheek teeth coronal elongation. Increased curvature (bending of the axis) is based on this theory, caused by the increase in occlusal pressure and an increase in intrusive forces to the cheek teeth because of cheek teeth coronal elongation. Due to this pressure and abnormal forces mandibular cheek teeth bend in lingual and maxillary cheek teeth in buccal directions (Crossley 1995). This coronal elongation and tooth bending either lingually or bucally is caused, based on this theory, by insufficient lateral (side-to-side) jaw movements during mastication resulting from a lack of fibre. Moreover, physiologically, the enamel layer is thicker at the lingual aspect of mandibular and buccal aspect of maxillary cheek teeth, which, in association with improper jaw movements and lack of wear of those particular teeth exacerbates spike formation with further soft tissue damage and erosions/ulcerations.

Coronal elongation of the cheek teeth may also lead to functional prognathism of the mandible leading to incisor malocclusion in a rostro-caudal direction (Fig. 1). In some cases, cheek teeth malocclusion (or temporomandibular joint damage) results in lateral jaw dislocation with incisor malocclusion in a meso-distal (lateral) direction.

As the occlusal force increases on the elongating teeth the eruption rate decreases or coronal eruption is arrested completely. Within a two- to fourfold rate change there is some physiological capacity to cope and minimal change within the newly forming tooth; the changes being reduction in length of the pulp by dentin deposition and increased curvature of the tooth. Despite the change in eruption rate, tooth growth and deposition of tooth substance continue at the apex which leads to the compression of germinal tooth tissue which further promotes apical tooth growth (Crossley 2005). Apical tooth growth can be so severe that the tooth apices penetrate the mandibular or maxillary periosteum and compress the outer soft tissues (Figs 2 and 3). The rate of tooth growth, the intrusive force and the ability of apical bone to remodel have a major effect on what appears clinically with concurrent disease and dietary imbalances also influencing the outcome (Crossley 1995).

image

Figure 2. Lateral view of a rabbit nasal cavity with radiopaque mass formation in the rostral intranasal area (CR, plate 5·7 ë 7·6 cm, scanner Durr CR 7 VET). Intranasal lesions, which are associated with incisors or cheek teeth, are indicative for osteomyelitis, neoplasia or pseudoneoplastic lesions. In this case, elodontoma (based on histopathological examination) formation resulted from regular (every week) incisor trimming with scissors.

Download figure to PowerPoint

image

Figure 3. Lateral oblique view of the left mandible. In the view with the angle of 40° it is possible to see reserve crowns and and third cheek teeth). (CR, plate 5·7 ë 7·6 cm, scanner Durr CR 7 VET)

Download figure to PowerPoint

Even a minor degree of cheek tooth clinical crown elongation has serious detrimental effects on incisor occlusion and jaw function (markedly reduced chewing efficiency) both of which further impede tooth wear. Gingival and alveolar bone growth frequently accompanies elongation of the cheek teeth so there is little visible clinical crown elongation in many affected individuals and radiography is required to confirm the changes (Crossley 2005). However, this theory has not yet been scientifically proven in cheek teeth of rabbits or other small herbivorous mammals with elodont dentition.

Metabolic bone disease as a cause of dental disease in rabbits

The ‘selective feeding’ theory

Harcourt-Brown (2009) suggested that the diet of many pet rabbits is low in calcium and vitamin D because of the selective feeding behaviour of rabbits offered mixed rations. Selective feeding can develop because rabbits have a natural tendency to choose the higher energy food item with lesser fibre content and individual rabbits may develop preferences, picking out the favoured ingredients only and rejecting the remainder of the commercial mixed food, hay included (Carpenter & Kolmstetter 2000). Another reason suggested for selective feeding is the presence of medical problems, especially dental disease (Harcourt-Brown 2007b). In most clinical cases of dental disease, hay is the main food refused by rabbits. Dietary intake therefore becomes based on cereals (if traditional rabbit mixed pellet and cereal food is fed), especially with higher amounts of peas, maize, wheat bran (and similar ingredients), which have a reversed calcium to phosphorus ratio (1:3 and more) and/or is absolutely calcium deficient, and could therefore lead to the development of nutritional secondary hyperparathyroidism (NSHP). Diets based on cereals and commercial mixture are also non-abrasive resulting in decreased chewing movements and so may lead to tooth elongation. Not only do hay and grass provide appropriate fibre and dental wear for rabbits, they are also an appropriate source of balanced calcium and phosphorus. Clearly, the effects of selective feeding are reduced if the rabbit is offered complete commercial pellets, hay and grass rather than a mix of cereals and pellets or better still grass or hay only diets. This depends on full access to grass (virtually impossible for the pet hutch rabbit) or good quality hay. Larger breed rabbits, mutated in size away from the wild-type rabbit, may however, require a higher protein content; therefore some pellets should be added to their hay diet.

The ‘pet rabbits have vitamin D and calcium deficiency’ theory

The conclusion of Harcourt-Brown (2006) is that metabolic bone disease plays a major role in the development of dental disease in pet rabbits. These findings are supported by a study of morphological and radiographic features of prepared intact skulls of pet rabbits. As dental disease increased in severity, the signs of osteopenia in the skull were recorded more commonly leading to the conclusion that the loss of supporting alveolar bone rather than increased occlusal pressure allows apical elongation (Harcourt-Brown 2009). Indeed, root elongation was found in all rabbits with dental disease, even in those with normal reserve crowns, and was the first dental change noted to take place. The study also showed that progressive loss of alveolar bone is a feature of the progressive syndrome of dental disease. Similarly, in other species, alveolar bone is known to be particularly susceptible to metabolic bone disease and results in displacement of the teeth. In rabbits, the visual and radiographic changes that take place in the teeth and bones of the skull suggest that metabolic bone disease is the cause of root elongation. Forces generated during biting and chewing would cause root elongation because there is insufficient alveolar bone to support the apices of the teeth. Further, it can be argued that the curvature of the teeth takes place in response to forces generated during chewing and biting and as curved teeth do not meet opposing teeth correctly, this leads to malocclusion and spur formation (Harcourt-Brown 2009).

Harcourt-Brown (2006) also described that calcium and/or vitamin D deficiency is the most likely cause of the metabolic bone disease and bone loss, although other factors (e.g. chewing forces, genetic, hormonal influences) may also play a part. It is suggested that rabbits are susceptible to calcium deficiency because the continual eruption and rapid growth of all the teeth requires a high demand for calcium to mineralise new dental tissue. Indeed, the efficient absorption of calcium in the intestines of rabbits is a way of meeting that demand. Although vitamin D plays a minor role in intestinal absorption of calcium in rabbits, it is used to boost absorption of calcium if dietary levels are very low. In addition to its role in calcium absorption, vitamin D also has a direct effect on the mineralisation of bones and teeth.

The diet of pet rabbits can be severely calcium deficient because grains and legumes are often used as rabbit food. Some popularly fed fruit and vegetables (e.g. apples and carrots) also have low calcium content (Harcourt-Brown 1996). Undetectable (i.e. very low) vitamin D concentrations have been recorded in housed pet rabbits.

The primary risk factors for low bone mineral density, osteoporosis and osteopenia include vitamin D insufficiency, inadequate calcium intake, lack of exercise and other dietary factors. Another benefit of vitamin D is maintenance of optimal muscle strength. Vitamin D deficiency can cause osteomalacia, which is associated with muscle and bone pain. Vitamin D deficiency may play a role in calcium metabolism disorders of pet rabbits. Experimental chronic vitamin D deficiency in the adult rabbit results in intestinal phosphorus malabsorption with a resulting renal phosphorus conservation. Rabbits fed a diet with 1·0% calcium, 0·5% phosphorus and no vitamin D develop osteomalacia as a result of hypovitaminosis D (Brommage et al. 1988). Although some vitamin D-deficient rabbits are able to maintain homeostasis, in others the resulting hypophosphataemia leads to inadequate skeletal mineralisation and the classical signs of osteomalacia (Bourdeau et al. 1986, Brommage et al. 1988).

Experimentally, a low calcium diet induced NSHP in young rabbits resulted in hypocalcaemia, hypophosphataemia, elevated alkaline phosphatase activity and PTH and calcitriol concentrations (Mehrotra et al. 2006). However, no data regarding the level of dietary phosphorus or vitamin D were given. In a study by Wu et al. (1990), adult rabbits on a low calcium diet (0·1%) readily developed osteoporotic changes, however, they were also fed an inverted calcium:phosphorus in a ratio of 1:5.

Several other authors indicate that osteoporosis may result in decreased oral bone density and alveolar bone loss (Cai 1992, Bai et al. 2006). Ashcraft et al. (1992) described that osteoporosis affects the rate of tooth movement through the involvement of alveolar bone and consequent periodontal and dental problems influence the response even to the physiological orthodontic forces. Moreover, studies in rats showed that the age-dependent decrease in alveolar bone turnover activity, in response to mechanical forces, may also affect the amount of tooth movement (Sidiropoulou-Chatzigiannis et al. 2007).

Other aetiological factors for osteoporosis that have been observed under experimental conditions include limited movement (caged animals), ovariectomy, ageing and glucocorticoid administration (Strates et al. 1988, Rothfritz et al. 1992, Southard et al. 2000, Cao et al. 2004, Castañeda et al. 2008). Osteoporosis induced by ovariohysterectomy has particular relevance to the pet rabbit where this surgery is common and recommended to prevent uterine adenocarcinoma. It is also interesting to speculate whether stress, and hence endogenous glucocorticoids, could induce bone changes in pet rabbits.

Alternate view – pet rabbits have excess calcium and vitamin D

The results of Schroeder (2000), Kamphues (1991, 2001) and Kamphues & Wolf (2003) claim that commercial diets for rabbits actually contain enough or more calcium, phosphorus and/or vitamin D than is required by a rabbit (taking into account the peculiar calcium metabolism of the rabbit compared with other mammals). The severity of problems due to excess of vitamin D is more pronounced when calcium is also fed to excess.

Feeding rabbits with excess calcium and/or vitamin D or subcutaneous administration of vitamin D is not recommended because soft tissue metastatic calcification readily develops and could be the cause of acute death (Garibaldi & Goad 1988, Zimmerman et al. 1990, Eason 1993, Rajasree et al. 2002). Subcutaneous iatrogenic vitamin D administration of 52 mg/kg led within a few days to signs of cardiovascular insufficiency, manifested as ascites and lung oedema, anorexia, mucous diarrhoea, loss of weight and apathy (Peixoto et al. 2010). Arteries, heart, lungs and stomach were affected with ectopic mineralisation.

Confusingly, Aithal et al. (2008) showed that over-supplementation of growing rabbits with dietary calcium and vitamin D could lead to osteopenia, which was apparent in the long bone radiographs. Aithal et al. (2008) stated that this could be probably due to imbalances in the calcium-phosphorus ratio and vitamin D leading to reduced skeleton mineralisation.

Kamphues et al. (1986) suggest that in hypervitaminosis D, the osteoblasts and bone marrow undergo degeneration, leading to necrosis and calcification. After vitamin D withdrawal, osteoblasts reappear and become overactive, leading to over-ossification. Osteosclerotic lesions (dense epiphyses and metaphyses, thickened bony articular surfaces, dense and thickened cortical bone, etc.) were seen in rabbits with experimental hypervitaminosis D in another study (Jiang et al. 1990).

Kamphues et al. (1986) also describe that in rabbits fed high amounts of dietary calcium, high-calcium concentrations in aortic tissue and kidney were noted. Moreover, dietary vitamin D levels as high as 1000 IU/kg and more led, independently of the dietary calcium concentration, to enhanced calcium content in aortic tissue.

Calcium oversupply will result in large amounts of urinary sediment, which is reported to be one of the predisposing factors for urolith formation or sludgy urine and is indeed commonly noted in pet rabbits. However, in a recent experimental study (Clauss et al. 2011), rabbits fed with alfalfa hay only (dietary calcium 2·32%, dietary phosphorus 0·28%) without additional supplementation of vitamin D did not develop kidney calcification and had good health status. Higher dietary calcium content resulting in higher urinary mineral content might not be considered pathological as additional factors rather than just high-dietary calcium concentrations are required to trigger urolithiasis (Clauss et al. 2011). Nevertheless these findings indicate that individual pet rabbits may be on a calcium-rich diet.

Effects of dietary phosphorus on dental disease

It has been suggested that rabbits are tolerant of a high-phosphorus diet (Chapin & Smith 1967a,1967b) and are efficiently adapted to low calcium diets (Barr et al. 1991). Barr et al. (1991) concluded that there are appropriate intestinal and renal homeostatic adaptations to dietary calcium deprivation in the growing rabbit and that the renal mechanisms are more rapidly induced and ultimately more efficient than the intestinal pathway. As a defence mechanism in healthy animals, rabbits fed a low calcium diet develop elevated serum PTH and calcitriol concentrations and renal calcium excretion is decreased. In those rabbits fed a high-calcium diet serum calcitriol concentrations decreased and renal calcium excretion increased (Gilsanz et al. 1991).

When rabbits are fed a 0·6% calcium and 1·2% high-phosphorus diet they readily (within 3 weeks) develop NSHP (Bas et al. 2005). This is characterised by hyperphosphataemia, increased creatinine concentration, decreased calcitriol concentration and parathyroid gland hyperplasia (Bas et al. 2005). Associated hyperphosphataemia arises not only because of an inability of PTH to excrete the entire phosphate load but also because of decreased renal function (Bas et al. 2005). Continuous PTH secretion contributes to the development of osteoporosis. Confirmation of NSHP in rabbits is based on basal (intact) PTH measurement and on disease confirmation by various imaging methods and on bone histology. Ionised and total calcium concentrations will be low or normal. However, in advanced NSHP (dietary calcium to phosphorus ratio 1:7), Bai et al. (2006) described higher total calcium concentrations with high basal PTH concentrations reaching 201·3 pg/mL. PTH concentrations higher than 430 pg/mL could be explained by concurrent renal failure (Bas et al. 2005) even when fed a dietary calcium to phosphorus ratio of 1:2. Bai et al. (2012) fed rabbits with an inappropriate calcium to phosphorus ratio of 1:7 and all rabbits developed NSHP that was defined by hyperplasia and hypertrophy of all parathyroid glands with marked PTH elevation (175 pg/mL in contrast to 17·7 pg/mL in the control group). After 4 months of feeding such a diet, serum phosphorus concentrations decreased and calcium concentrations increased, which could be explained by the effect of the PTH on calcium reabsorption and phosphorus excretion in kidneys (Bai et al. 2012). Bai et al. (2012) also showed that kidney tubules were partially mineralised, however, there were no signs of kidney failure as described in degus (Gumpenberger et al. 2012).

In horses, loss of alveolar socket bone is an early change associated with NSHP and occurs before other skeletal changes (Krook & Lowe 1964). It seems, therefore, that it is the level of phosphorous, or the relative elevation of phosphorous to calcium that is more important in the development of calcium metabolic disorders in rabbits and small herbivorous rodents with elodont dentition rather than the low dietary calcium per se.

Dental disease in small herbivorous rodents with elodont dentition and the effect of high-phosphorus diet and improper calcium to phosphorus ratio

Dental disease is also present in other small herbivorous mammals kept as pet animals with a very high incidence in degus, guinea pigs and chinchillas (Jekl et al. 2008, 2011b).

The impact of pelleted diets with different mineral compositions on the incisor tooth structure, on the crown size of the mandibular cheek teeth, as well as the mandibular bone and cheek teeth density, in degus (Octodon degus) has been investigated experimentally (Jekl et al. 2011a,2011c, Gumpenberger et al. 2012). Degus in these studies were fed high-phosphorus diets with dietary calcium to phosphorus ratio 1:1 for 14 months. Dental disease in groups fed by this diet had obvious reserve crown elongation of all teeth and had significantly smaller relative cheek teeth and mandibular densities (osteoporosis) than animals fed normal diets. However, these osteoporotic changes were detectable by computed tomography. Moreover, disturbed mineral metabolism resulted in enamel depigmentation, enamel hypoplasia, enamel pitting and altered dentin morphology. High-phosphorus diets resulted also in parathyroid gland hyperplasia and kidney calcification as was also described in rabbits (Bai et al. 2012, Gumbenberger et al. 2012), which could further aggravate metabolic bone disease.

Results of these studies suggested that more attention should be focused on dietary phosphorus content when facing altered tooth structure in small mammals. Because of the same structural problems and coronal and apical teeth elongation, similar calcium metabolism (especially in degus – calcium excretion via urine, Hommel et al. 2011) it is suggested that the aetiology of such pathologies should be the same in small herbivorous rodents with elodont dentition as in rabbits.

Metabolic bone disease and other bone lesions

Jaws and teeth of elodont herbivorous mammals are specifically adapted to the prehension and processing of high-fibre diet. Because jaws are constantly remodelling because of various pressures acting during mastication and because of continuous teeth eruption, it seems, that these tissue are much susceptible to metabolic bone changes than other bones in the rabbit [similar to metabolic bone disease in reptiles and dogs (rubber jaw), where particular bones are more affected than others]. However, Harcourt-Brown (2006) described that rabbits affected with dental disease also developed decalcification of the vertebral skeleton. Southard et al. (2000) showed that in experimental osteoporotic female rabbits, mandibular bone mineral density decreases in relation to spinal density. On the basis of experimental studies in rodents (Jekl et al. 2011a) early and mild, and occasionally, even more severe changes may be detectable only by advanced imaging methods and/or histopathological bone examination rather than by radiography.

Developing a joint theory

It is suggested that dental problems in rabbits could be caused by a combination of one or other of metabolic bone disease and lack of wear. However, metabolic bone disease appears to play a more important role than was previously believed by many authors. The constantly growing rabbit tooth is continually under orthodontic forces – factors affecting tooth position, apart from dental tissue itself, includes the periodontal ligament, germinative tissue, bone and applied force (Wiggs & Lobprise 1997a). As trabecular bone (including that of the jaws) is in constant turnover the rabbit dental system is prone to impairment by any factor affecting bone and/or tooth.

Under physiological conditions, the attrition and eruption rate (2 to 4 mm per week for incisors and 3 to 4 mm per month for cheek teeth) are the same and dental tissues and alveolar and supporting bone are healthy. An intrusive force (pathological or physiological) which presses the tooth into the socket and causes activation of osteoclasts and subsequent bone resorption (apical tooth elongation) must therefore be present in either cases with reduced tooth wear or in cases with metabolic bone disease or their combinations.

The resulting enamel points (spikes) mechanically restrict the normal side-to-side jaw movements in a vicious self-perpetuating cycle, which affect the ability of the teeth to occlude and grind properly. Moreover, animals start to be more selective in feeding and refuse to eat hay and grass but prefer feeding on softer items which may have an improper calcium to phosphorus ratio or low calcium concentrations, leading to reduced and/or further improper wear and metabolic disturbances. Feed items are also chewed for less time resulting in improper wear (Reiter 2008). So, as the disease progresses, both metabolic bone disease and lack of wear play an important role in dental disease.

The relationship between systemic disease/systemic stress and oral bone loss/germinative tooth tissue pathology is a complex problem. Deterioration of tooth quality and abnormalities in tooth eruption (irregular hyperplasia of dentin arrangement, enamel loss, horizontal ridges on incisors, etc.) are present because of pathological changes of tooth germinative tissue or periodontal attachment (Fig 4), which could be caused by metabolic bone disease (Harcourt-Brown 2009, Jekl et al. 2011a, 2011c), trauma, inflammation, vascular damage or ageing changes (Wiggs & Lobprise 1997b). In degus, metabolic bone disease, apart from alveolar bone changes (osteoporosis), causes significant changes in dentin and enamel with subsequent dental disease development and/or general dental disease aggravation (Jekl et al. 2011c). Moreover, all systemic diseases, which influence calcium metabolism, should be included in the list of differential diagnoses (e.g. chronic kidney failure, hyperadrenocorticism, secondary hyperparathyroidism, hypervitaminosis D, hypovitaminosis D, acid-base disturbances).

image

Figure 4. Intraoral dental digital radiograph of the right mandibular arcade performed with parallel technique (CR, plate 2 ë 3 cm, scanner Durr CR 7 VET). This rabbit was fed only pelleted diet and bananas. Alterations of occlusal plane of the cheek teeth, apical elongation of all teeth and apical dysplastic changes as thinning of pulpal cavity, changes in apical teeth structure, periapical lucency (arrows), widening of the interproximal coronal spaces, irregular cheek teeth surface and absence of enamel folds in the cheek teeth were obvious. Osteoresorptive lesions of first and third mandibular cheek teeth were apparent (asterix)

Download figure to PowerPoint

The main aetiological factors for acquired dental disease may be grouped as:

  1. Normal attrition plus metabolic bone disease and other systemic disease
  2. Reduced attrition plus optimal bone health
  3. Reduced attrition plus metabolic bone disease and other systemic disease
  4. Abnormal eruption plus metabolic bone disease and other systemic disease
  5. Tooth structure impairment plus any of the above

Conclusion

Rabbits have very efficient calcium absorption perhaps as an adaptation to evolving on a low calcium diet. They usually passively absorb all the dietary calcium available (independent of vitamin D) and the active vitamin D dependant calcium transport occurs only in rabbits fed a very low calcium diet. At relatively high-dietary calcium (for a rabbit) the intestine continues to absorb calcium and excretes the excess via the kidneys. The optimal dietary concentration appears to be 0·6 to 1% for calcium, 0·3 to 0·4 for phosphorus and 600 to 800 IU/kg for vitamin D. The calcium:phosphorus dietary ratio should be at least 1·5-2:1 for normal homeostasis. It is not recommended to feed rabbits additional calcium, phosphorus and/or vitamin D (calcitriol) because of the risk of soft tissue metastatic calcification, unless it is indicated in association with severe renal disease. It seems that the main aetiopathological factors for the development of subsequent nutritional metabolic disturbances are the reversed calcium to phosphorus ratio present in many commercial mix diets or consumed during selective feeding and high-dietary vitamin D, and not low dietary calcium per se.

It therefore also follows that in contrast to other mammals, pet rabbits with chronic renal failure (CRF) may develop hypercalcaemia with hypophosphataemia if maintained on a diet suitable for optimal calcium metabolism. Indeed, in clinical practice it appears that in some pet rabbits, hypercalcaemia, osteosclerosis and nephrocalcinosis are common findings in renal failure indicating that these rabbits are in fact receiving a normal/high amount of dietary calcium and/or phosphorous routinely in the pet environment. There is a need to establish an appropriate diet for rabbits with different syndromes of CRF, particularly a low-phosphorus diet to prevent further renal damage and metastatic calcification.

Metabolic bone disease together with the reduction in chewing movements/lack of wear that leads to insufficient or abnormal dental wear and tooth substance deterioration are responsible for the onset of dental problems in pet rabbits. Intrusive forces which press the tooth into the socket and cause activation of osteoclasts and subsequent bone resorption (apical tooth elongation) are present in cases with reduced tooth wear or in cases with metabolic bone disease or their combinations. Resulting enamel points (spikes), from whatever reason, mechanically restrict the normal side-to-side lateral jaw movements in a vicious self-perpetuating cycle. Apical pressure on intra-alveolar nerves and pressure on periosteum may lead to pain and disinhibition of grinding fibrous material. Moreover, animals start to be more selective in feeding and refuse to eat hay and grass resulting in reversed calcium to phosphorus ratio or low calcium diet. This leads to further improper tooth wear and metabolic disturbances. So, as the disease progress, metabolic bone disease, lack of wear and tooth substance deterioration play important roles in health impairment.

Deterioration of tooth quality and abnormalities in tooth eruption could be associated with a wide range of systemic disease and stress-related disorders. Enamel and dentin quality must be evaluated in all patients and it appears that pathologies of these tissues play an important role in pathogenesis of dental disease.

Selective feeding should be eliminated in all cases by offering hay, meadow grass and vegetables. Complete commercial pellets with proper calcium to phosphorus ratio could also be offered in a small amount. As a rough guide, ad libitum timothy based hay mixed with other types of hay, 1 cup of varied fresh vegetables and/or edible plants, and 25 g of a pelleted diet per kilogram of bodyweight per day is considered appropriate for a rabbit (Campbell-Ward 2012).

Care should be taken when assessing diet and assessing calcium and phosphorus content. Veterinary practitioners and clients should be aware, that some vegetables contain a proper calcium to phosphorus ratio in dry matter basis (e.g. kale – calcium 146 mg/100 g and phosphorus 89 mg/100 g; broccoli – calcium 105 mg/100 g and phosphorus 89 mg/100 g); however, they contain a very high water content (90%). It means that 100 g of fresh kale contain 10 g dry matter; 14·6 mg calcium and 8·9 mg phosphorus and that rabbits are mostly not capable of eating such large volumes to reach their physiological calcium demand (Harcourt-Brown 2013).

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Physiology Of Calcium And Phosphorus Metabolism
  5. Dental Disease
  6. Acknowledgement
  7. References

The authors would like to thank Mrs Frances Harcourt-Brown for critical reading of the manuscript and helpful suggestions.

Conflict of interest

None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Physiology Of Calcium And Phosphorus Metabolism
  5. Dental Disease
  6. Acknowledgement
  7. References
  • Aithal, H. P., Kinjavdekar, P., Amarpal Pawde, A. M., et al. (2008) Effects of nandrolone and TGF-beta1 in growing rabbits with osteopenia induced by over-supplementation of calcium and vitamin D3. Veterinary Research Communications 33, 331-343
  • Ashcraft, M. B., Southard, K. A. & Tolley, E. A. (1992) The effect of corticosteroid-induced osteoporosis on orthodontic tooth movement. American Journal of Orthodontics and Dentofacial Orthopedics 102, 310-319
  • Bai, R. J., Cong, D. G., Shen, B. Z., et al. (2006) Bone diseases in rabbits with hyperparathyroidism: computed tomography, magnetic resonance imaging and histopathology. Chinese Medical Journal 119, 1248-1255
  • Bai, R. J., Cheng, X. G., Yan, D., et al. (2012) Rabbit model of primary hyperparathyroidism induced by high-phosphate diet. Domestic Animal Endocrinology 42, 20-30.
  • Barr, D. R., Sadowski, D. L., Hu, J., et al. (1991) Characterization of the renal and intestinal adaptations to dietary calcium deprivation in growing female rabbits. Mineral and Electrolyte Metabolism 17, 32-40
  • Bas, S., Bas, A., Estepa, J. C., et al. (2004) Parathyroid gland function in the uremic rabbit. Domestic Animal Endocrinology 26, 99-110
  • Bas, S., Bas, A., López, I., et al. (2005) Nutritional secondary hyperparathyroidism in rabbits. Domestic Animal Endocrinology 28, 380-390.
  • Bass, J. K. & Chan, G. M. (2006) Calcium nutrition and metabolism during infancy. Nutrition 22, 1057-1066
  • Bourdeau, J. E., Schwer-Dymerski, D. A., Stern, P. H., et al. (1986) Calcium and phosphorus metabolism in chronically vitamin D-deficient laboratory rabbits. Mineral and Electrolyte Metabolism 12,176-185
  • Brommage, R., Miller, S. C., Langman, C. B., et al. (1988) The effects of chronic vitamin D deficiency on the skeleton in the adult rabbit. Bone 9, 131-139
  • Bronner, F. (1998) Calcium absorption – a paradigm for mineral absorption. The Journal of Nutrition 128, 917-920
  • Buss, S. l. & Bourdeau, J. E. (1984) Calcium balance in laboratory rabbits. Mineral and Electrolyte Metabolism 10, 127-132
  • Cai, J. J. (1992) Effect of vitamin D over-dosage on the tooth and bone development of rabbits. Abstract. Zhonghua Kou Qiang Yi Xue Za Zhi 27,296-299
  • Campbell-Ward, M. L. (2012) Gastrointestinal physiology and nutrition. In: Ferrets, Rabbits, and Rodents. Clinical Medicine and Surgery. 3rd edn. Eds K. E. Quesenberry and J. W. Carpenter. Elsevier Saunders, St. Louis, MO, USA. pp 183-192
  • Cao, T., Shirota, T., Ohno, K., et al. (2004) Mineralized bone loss in partially edentulous trabeculae of ovariectomized rabbit mandibles. Journal of Periodontal Research 39, 37-41
  • Capello ,V. & Lennox, A. (2012) Small mammal dentistry. In: Ferrets, Rabbits, and Rodents. Clinical Medicine and Surgery. 3rd edn. Eds K. E. Quesenberry and J. W. Carpenter. Elsevier Saunders, St. Louis, MO, USA. pp 452-471
  • Carpenter, J. W. & Kolmstetter, C. M. (2000) Feeding small exotic mammals. In: Small Animal Clinical Nutrition. 4th edn. Eds M. S. Hand, C. D. Tchatcher, R. L. Remillard, et al. Walsworth Publishing Company, Marceline, MO, USA. pp 943-960
  • Castañeda, S., Calvo, E., Largo, R., et al. (2008) Characterization of a new experimental model of osteoporosis in rabbits. Journal of Bone and Mineral Metabolism 26, 53-59
  • Chapin, R. E. & Smith, S. E. (1967a) Calcium requirement of growing rabbits. Journal of Animal Science 26, 67-71
  • Chapin, R. E. & Smith, S. E. (1967b) High phosphorus diets fed to growing rabbits. The Cornell Veterinarian 57, 492-500
  • Clauss, M., Burger, B., Liesegang, A., et al. (2011) Influence of diet on calcium metabolism, tissue calcification and urinary sludge in rabbits (Oryctolagus cuniculus). Journal of Animal Physiology and Animal Nutrition, DOI: 10.1111/j.1439-0396.2011.01185.x. [Epub ahead of print]
  • Crossley, D. A. (1995) Clinical relevant aspects of lagomorph dental anatomy: the rabbit (Oryctolagus cuniculus). Journal of Veterinary Dentistry 12, 137-140.
  • Crossley, D. A. (2003a) Oral biology and disorders of lagomorphs. Veterinary Clinics of North America: Exotic Animal Practice 6, 629-660
  • Crossley, D. A. (2003b) Dental disease in chinchillas. PhD thesis. University of Manchester, UK
  • Crossley, D. A. (2005) Pathophysiology of continuously growing teeth. Proceedings of 2nd Slovenian – Croatian Congress on Exotic Pets and Wild Animals. Ljubljana, Slovenia, September 26-29, 2005. pp 21-28
  • Crossley, D. A. & Aiken, S. (2003) Small mammal dentistry. In: Ferrets, Rabbits and Rodents. Clinical Medicine and Surgery. 2nd edn. Eds K. E. Quesenberry and J. W. Carpenter. W.B. Saunders, St. Louis, MO, USA. pp 370-382
  • Eason, C. T. (1993) The acute toxicity of cholecalciferol to the European rabbit (Oryctolagus cuniculus). Wildlife Research 20, 173-176
  • Eckermann-Ross, C. (2008) Hormonal regulation and calcium metabolism in the rabbit. Veterinary Clinics of North America Exotic Animal Practice 11, 139-152.
  • Fairham, J. & Harcourt-Brown, F. M. (1999) Preliminary investigation of the vitamin D status in pet rabbits. Veterinary Record 145, 424-454
  • Fujisawa, T., Kuboki, T., Kasai, T., et al. (2003) A repetitive, steady mouth opening induced an osteoarthritis-like lesion in the rabbit temporomandibular joint. Journal of Dental Research 82, 731-735
  • Garibaldi, B. A. & Goad, M. E. (1988) Hypercalcemia with secondary nephrolithiasis in a rabbit. Laboratory Animal Science 38, 331-333
  • Gillet, C. S. (1994) Selected drug dosages and clinical reference data. In: The Biology of the Laboratory Rabbit. 2nd edn. Eds P. J. Manning, D. H. Ringler and C. E. Newcomer. Academic Press, San Diego, CA, USA. pp 467-472
  • Gilsanz, V., Roe, T. F., Antunes, J., et al. (1991) Effect of dietary calcium on bone density in growing rabbits. American Journal of Physiology 260, E471-E476
  • Goad, D. L., Pecquet, M. E. & Warren, H. B. (1989) Total serum concentrations in rabbits. Journal of American Veterinary Association 194, 1520-1521
  • Gumpenberger, M., Jeklova, E., Skoric, M., et al. (2012) Impact of a high-phosphorus diet on the sonographic and CT appearance of kidneys in degus, and possible concurrence with dental problems. Veterinary Record, 170, 153.
  • Harcourt-Brown, F. (1996) Calcium deficiency, diet and dental disease in pet rabbits. Veterinary Record 139, 567-571
  • Harcourt-Brown, F. (2002) Textbook of Rabbit Medicine. Reed Education and Professional Publishing Ltd., Oxford, UK. 410
  • Harcourt-Brown, F. (2006) Metabolic bone disease as a possible cause of dental disease in pet rabbits. Thesis for Fellowship of Royal College of Veterinary Surgeons, UK
  • Harcourt-Brown, F. (2007a) Radiographic signs of renal disease in rabbits. Veterinary Record 160, 7877-7894
  • Harcourt-Brown, F. (2007b) The progressive syndrome of acquired dental disease in rabbits. Journal of Exotic Pet Medicine 16, 146-157
  • Harcourt-Brown, F. (2009) Dental disease in pet rabbits 1. Normal dentition, pathogenesis and aetiology. In Practice 31, 370-379
  • Harcourt-Brown, F. (2013) Dietary calcium calculations: the rabbit as an example. Proceedings of the 1st International Conference on Avian, Herpetological and Exotic Mammal Medicine. Wiesbaden, Germany, April 20 to 26, 2013. pp 106-108
  • Harcourt-Brown, F. & Baker, S. J. (2001) Parathyroid hormone, haematological and biochemical parameters in relation to dental disease and husbandry in rabbits. Journal of Small Animal Practice 42, 130-136
  • Harris, I. (1994) The laboratory rabbit. ANZCCART News 7, 1-8
  • Hewitt, C. D., Innes, D. J., Savory, J., et al. (1989) Normal biochemical and hematological values in New Zealand White rabbits. Clinical Chemistry 35, 1777-1779
  • Holick, M. F. (2003) Vitamin D: a millennium perspective. Journal of Cellular Biochemistry. 88, 296-307
  • Hommel, D., Roefs, M., Wolf, P., et al. (2011) Basic data regarding nutrition of degus (Octodon degu). Proceedings of the 15th ESVCN Congress 2011, Zaragoza, Spain. p 151
  • How, K. L., Hazewinkel, H. A. & Mol, J. A. (1994) Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D. General and Comparative Endocrinology 96, 12-18
  • Jekl, V., Hauptman, K. & Knotek, Z. (2008) Quantitative and qualitative assessments of intraoral lesions in 180 small herbivorous mammals. Veterinary Record 162, 442-449
  • Jekl, V., Gumpenberger, M., Jeklova, E., et al. (2011a) Impact of pelleted diet of different mineral composition on the crown size of mandibular cheek teeth and mandibular relative density in degus. Veterinary Record, 168, 641
  • Jekl, V., Hauptman, K. & Knotek, Z. (2011b) Diseases in pet degus: a retrospective study in 300 animals. Journal of Small Animal Practice 52, 107-112.
  • Jekl, V., Krejcirova, L., Buchtova, M., et al. (2011c) Effect of high phosphorus diet on tooth microstructure of rodent incisors. Bone 49, 479-484
  • Jenkins, J. (2008) Rabbit diagnostic testing. Journal of Exotic Pet Medicine 17, 16-25
  • Jiang, Y. B., Wang, Y. Z., Zhao, J., et al. (1990) Metastatic calcification within bone. The main cause of osteosclerosis in hypervitaminosis D3. Radiologic-pathologic correlation. Investigative Radiology 25, 1188-1196
  • Kamphues, J. (1991) Calcium metabolism of rabbits as an etiological factor of urolithiasis. The Journal of Nutrition 121, S95-S96
  • Kamphues, J. (2001) The species-specific feeding of rabbits as pets. Deutsche Tierartzliche Wochenschrift 108, 131-135 (in German)
  • Kamphues, J. & Wolf, P. (2003) A critical assessment of commercial supplementary feedstuffs for rabbits, guinea pigs, chinchilla as companion pets. Kritische Einschätzung kommerzieller Ergänzungspräparate für Kaninchen, Meerschweinchen und Chinchilla. Praktischer Tierarzt 84, 674-678 (in German)
  • Kamphues, J. Carstensen, P., Schroeder, D., et al. (1986) Effects of increasing calcium- and vitamin D supply on calcium metabolism of rabbits. Journal of Animal Physiology 56, 191-208 (in German)
  • Krook, L. & Lowe, J. E. (1964) Nutritional secondary hyperparathyroidism on the horse. Pathologia Veterianaria 1(Suppl), 1-98
  • Langenbach, G., van de Pavert, S., Savalle, W., et al. (2003) Influence of food consistency on the rabbit masseter muscle fibres. European Journal of Oral Science 111, 81-84
  • Latour, M. A., Hopkins, D., Kitchens, T., et al. (1998) Effects of feeding a liquid diet for one year to New Zealand White rabbits. Laboratory Animal Science 48, 81-84
  • Lindsey, J. R. & Fox, R. R. (1994) Inherited diseases and variations. In: The Biology of the Laboratory Rabbit. 2nd edn. Eds P. J. Manning, D. H. Ringler and C. E. Newcomer. Academic Press, San Diego, CA, USA. pp 293-320
  • Lowe, J. A. (1998) Pet rabbit feeding and nutrition. In: The Nutrition of the Rabbit. Eds C. de Blas and J. Wiseman. CABI Publishing, Oxon, UK. pp 309-331
  • Marounek, M., Duskova, D. & Skrivanova, V. (2003) Hydrolysis of phytic acid and its availability in rabbits. British Journal of Nutrition 89, 287-294
  • Marounek, M., Brenova, N., Suchorska, O., et al. (2009) Phytase activity in rabbit caecal bacteria. Folia Microbiologica 54, 111-114
  • Mateos, G. G. & de Blas, C. (1998) Minerals, vitamins and additives. In: The Nutrition of the Rabbit. Eds C. de Blas and J. Wiseman. CABI Publishing, Oxon, UK. pp 145-176
  • Mateos, G. G., Rebollar, P. G. & de Blas, C. (2010) Minerals, vitamins and additives. In: Nutrition of the Rabbit, 2nd edn. Eds C. de Blas and J. Wiseman. CABI Publishing, Oxon, UK. pp 119-150
  • Mathieu, L. G. & Smith, S. E. (1961) Phosphorus requirements of growing rabbits. Journal of Animal Science 20, 510-513
  • McLean, F. C. & Hastins, A. B. (1935) The state of calcium in the fluids of the body. I. The conditions affecting the ionization of calcium. The Journal of Biological Chemistry 108, 322
  • Mehrotra, M., Gupta, S. K., Kumar , et al. (2006) Calcium deficiency-induced secondary hyperparathyroidism and osteopenia are rapidly reversible with calcium supplementation in growing rabbit pups. British Journal of Nutrition 95, 582-590
  • Minarikova, A., Hauptman, K., Proks, P., et al. (2012) Facial abscess in a rabbit. IX Congres International sur les animaux sauvages et Exotiques. Paris, France, March 8 to 10,2012. . pp 36-37
  • Norris, S. A., Pettifor, J. M., Gray, D. A., et al. (2001) Calcium metabolism and bone mass in female rabbits during skeletal maturation: effects of dietary calcium intake. Bone 29, 62-69
  • Okuda, A., Hori, Y., Ichihara, N., et al. (2007) Comparative observation of skeletal-dental abnormalities in wild, domestic, and laboratory rabbits. Journal of Veterinary Dentistry 24, 224-229.
  • Pearce, L. & Brown, W. H. (1948) Hereditary osteopetrosis of the rabbit; general features and course of disease; genetic aspects. Journal of Experimental Medicine 88, 579-596.
  • Peixoto, P. V.,Klem, M. A. P., Brito M. F., et al. (2010) Toxicological, clinic-pathological and ultrastructural aspects of iatrogenic and experimental poisoning by vitamin D in rabbits. Pesquisa Veterinária Brasileira 30, 277-288.
  • Poikela, A., Pirttiniemi, P. & Kantomaa, T. (2000) Location of the glenoid fossa after a period of unilateral masticatory function in young rabbits. European Journal of Orthodonthics 22, 105-112
  • Rajasree, S., Umashankar, P. R., Lal, A. V., et al. (2002) 1,25-dihydroxyvitamin D3 receptor is upregulated in aortic smooth muscle cells during hypervitaminosis D. Life Sciences 70, 1777-1788
  • Reiter, A. (2008) Pathophysiology of dental disease in the rabbit, guinea pig and chinchilla. Journal of exotic Pet Medicine 17, 70-77
  • Ritskes-Hoitinga, J., Grooten, H. N., Wienk, K. J., et al. (2004) Lowering dietary phosphorus concentrations reduces kidney calcification, but does not adversely affect growth, mineral metabolism, and bone development in growing rabbits. British Journal of Nutrition 91, 367-376
  • Rothfritz, P., Loeffler, K. & Drescher, B. (1992) The effects of different housing systems on the structure of cancellous bones of chinchilla and New Zealand White rabbits. Tieartztliche Umschau 47, 758-761
  • Schroeder, A. (2000) Vergleichende Untersuchungen zur Futteraufnahme von Zwergkaninchen, Meerschweinchen und Chinchilla bei Angebot unterschiedlich konfektionierter Einzel- und Mischfuttermittel. Thesis, Tierärztliche Hochschule, Hannover. p 177 (in German)
  • Sidiropoulou-Chatzigiannis, S., Kourtidou, M. & Tsalikis, L. (2007) The effect of osteoporosis on periodontal status, alveolar bone and orthodontic tooth movement. A literature review. Journal of the International Academy of Periodontology 9, 77-84
  • Southard, T. E., Southard, K. A., Krizan, K. E., et al. (2000) Mandibular bone density and fractal dimension in rabbits with induced osteoporosis. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology & Endodontics 89, 244-249
  • Strates, B. S., Stock, A. J. & Connolly, J. F. (1988) Skeletal repair in the aged: a preliminary study in rabbits. The American Journal of the Medical Sciences 296, 266-269
  • Tryfonidou, M. A., van den Broek, J., van den Brom, W. E., et al. (2002) Intestinal calcium absorption in growing dogs is influenced by calcium intake and age but not by growth rate. The Journal of Nutrition 132, 3363-3368
  • Verstraete, F. J. M. & Osofsky, A. (2005) Dentistry in pet rabbits. Compendium on Continuing Education for the Practicing Veterinarian 9, 671-684
  • Warren, H. B., Lausen, N. C., Segre, G. V., et al. (1989) Regulation of calciotropic hormones in vivo in the New Zealand white rabbit. Endocrinology 125, 2683-2690
  • Whiting, S. J. & Quamme, G. A. (1984) Effects of dietary calcium on renal calcium, magnesium and phosphate excretion by the rabbit. Mineral and Electrolyte Metabolism 10, 217-221
  • Wiggs, R. B. & Lobprise, H. B. (1997a) Basics of orthodonthics. In: Veterinary Dentistry Principles and Practice. Eds R. B. Wiggs and H. B. Lobprise. Lippincot-Raven, Philadelphia, PA, USA. pp 435-481
  • Wiggs, R. B. & Lobprise, H. B. (1997b) Dental and oral disease in rodents and lagomorphs. In: Veterinary Dentistry Principles and Practice. Eds R. B. Wiggs and H. B. Lobprise. Lippincot-Raven, Philadelphia, PA, USA. pp 518-537
  • Wolf, P. & Kamphues, J. (1996) Untersuchungen zu Fütterungseinflüssen auf die Entwicklung der Incisivi bei Kaninchen, Chinchilla und Ratte. Kleintierpraxis 41, 723-732 (in German)
  • Wolf, P. & Kamphues, J. (2009): Anfragen aus der tierärztlichen Fütterungsberatung zu kleinen Nagern. Kleintierpraxis 54, 317-321 (in German)
  • Wolf, P., Wenger, A. & Kamphues, J. (1997) Problems of crude fiber supply in dwarf rabbits, guinea pigs and chinchilla fed as pets. Vortragsabstracts der 10. Arbeitstagung über Haltung und Krankheiten der Kaninchen. Pelztiere und Heimtiere, Celle,May 14-15, 1997 (in German)
  • Wolf, P., Bucher, L. & Kamphues, J. (1999) Die Futter-, Energie- und Wasseraufnahme von Zwergkaninchen unter praxisüblichen Fütterungsbedingungen. Kleintier Praxis 44, 263-280 (in German)
  • Wu, D. D., Boyd, R. D., Fix, T. J., et al. 1990 Regional patterns of bone loss and altered bone remodeling in response to calcium deprivation in laboratory rabbits. Calcified Tissue International 47, 18-23
  • Zimmerman, T. E., Giddens, W. E. Jr, DiGiacomo, R. F., et al. (1990) Soft tissue mineralisation in rabbits fed a diet containing excess vitamin D. Laboratory Animal Science 40, 212-215