Nutrition and the skeletal health of dogs and cats Ronald Jan Corbee Colofon Copyright © 2014 All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any form by any means, without prior permission of the author. Lay-out: Proefschrift-aio.nl Cover: Proefschrift-aio.nl ISBN: 978-90-393-6174-0 Nutrition and the skeletal health of dogs and cats De invloed van voeding op het skelet van honden en katten (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 28 augustus 2014 des middags te 4.15 uur door Ronald Jan Corbee geboren op 28 april 1979 te Alkmaar Promotoren: Prof.dr. H.A.W. Hazewinkel Prof.dr. J.W. Hesselink Copromotoren: Dr. M.A. Tryfonidou Dr. A.B. Vaandrager Contents Chapter 1: General introduction, aim and scope of the study 7 Part I: Effects of nutrition on osteoarthritis Chapter 2: Obesity and osteoarthritis 15 Chapter 3: Obesity in show dogs 33 Chapter 4: Obesity in show cats 49 Chapter 5: The effect of dietary long-chain omega-3 fatty acids 61 supplementation on owner’s perception of behavior and locomotion in cats with naturally occurring osteoarthritis Part II: Vitamin A and D requirements in relation to skeletal health Chapter 6: The interaction of vitamin A and vitamin D with emphasis 79 on bone metabolism Chapter 7: Cutaneous vitamin D synthesis in carnivorous species 103 Chapter 8: Composition and use of puppy milk replacers in German 115 Shepherd puppies in the Netherlands Chapter 9: Dietary vitamin D supplementation during early growth 129 does not protect against medial coronoid disease in Labradors Chapter 10: Vitamin D status before and after hypophysectomy in dogs 149 with pituitary-dependent hypercortisolism Chapter 11: Ground reaction forces of walking cats; assessment and 163 comparison with walking dogs Chapter 12: Chronic vitamin A supplementation in cats results in 185 minor skeletal changes and liver fibrosis; the latter was counteracted by moderate vitamin D supplementation Chapter 13: General discussion 205 Summary 219 Samenvatting 225 Curriculum vitae and list of publications 231 Acknowledgements 235 6 Chapter 1 General introduction, aim and scope of the study 7 1 8 General introduction, aim and scope of the study Nutrition is about balance; nutritional imbalances can cause several pathological 1 changes in companion animals. In this thesis, the influence of nutrition on skeletal health is studied. Nutrition supplies building blocks for bone (e.g. calcium, phosphate) and provides essential co-factors for enzymes (e.g. copper and manganese) which influence bone cells to either produce (osteoblasts) or resorb (osteoclasts) extracellular matrix with the aid of vitamin A and vitamin D. In part I of this thesis the possible effects of nutrition on osteoarthritis, like high caloric intake and supplementation of long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are studied. In Part II of this thesis, the effects of imbalances of vitamin A and D on skeletal health are studied. Part I Obesity is a common disease in companion animal practice. It is a condition in which excess body fat has accumulated to the extent that it may be harmful to health, caused by an imbalance between energy intake and energy expenditure. In dogs and cats obesity often exacerbates osteoarthritis (OA). To elucidate the mechanisms by which OA and obesity are linked, a review of the literature will be performed (Chapter 2). Several dog and cat breeds are suggested to have an increased prevalence of obesity; however this is not substantially clarified by current scientific evidence. The aim of the study as described in Chapter 3 is to identify the dog breeds with an increased risk for obesity. The same for cat breeds in Chapter 4. As these studies are performed in show dogs and show cats, respectively, these studies also evaluate if what owners and judges regard as normal or beautiful does correspond with the optimal body condition. In dogs, OA is a common disease and several treatment options have been investigated and are generally accepted by clinicians. Recently, the high prevalence of OA in cats was identified (Slingerland et al. 2011), and it was clear that these cats demonstrate more subtle behavioral changes, rather than obvious lameness as can be observed in dogs suffering from OA. One of the nutraceuticals used in dogs suffering from OA are dietary long-chain omega-3 fatty acids EPA and DHA. EPA and DHA are the building blocks for prostaglandins and leukotrienes with anti-inflammatory effects. These free fatty acids have been proved to be effective in dogs suffering from OA by improving locomotion, as was demonstrated by force plate analysis (Roush et al. 2010). Furthermore, supplementation of EPA and DHA was effective by lowering the dosage of non-steroid anti-inflammatory drugs necessary to control lameness in dogs with OA (Fritsch et al. 2010). There is only little evidence for effects of EPA and DHA in cats with OA, as only one study measured the effects of a therapeutic diet (including EPA and DHA) on lameness in cats (Lascelles et al. 2010). The aim of the study described in Chapter 5 is to investigate if supplementation of EPA and DHA will have beneficial effects on behavior and locomotion in client-owned cats suffering from OA. 9 1 Part II Omnivore and herbivore species are able to synthesize vitamin D from 7-dehydrocholesterol in the skin under influence of UVB-light. Dogs and cats are unable to synthesize sufficient amounts of vitamin D in the skin, unlike rats (How et al. 1994). This is possibly caused by an increased activity of delta-7-dehydrocholesterol reductase (d7DHCr), as was demonstrated in cats who were able to synthesize sufficient amounts of vitamin D in the skin when they received an inhibitor of d7DHCr (Morris 1999). The aim of Chapter 7 is to identify if other carnivorous species than the canine and feline species are also unable to synthesize significant amounts of vitamin D in the skin. Nutrients influence bone metabolism, and thus the development of orthopedic diseases. Several studies demonstrate the detrimental effect of high and low calcium intake, as well as high vitamin D intake, on skeletal development in dogs (Hazewinkel et al. 1991, Schoenmakers et al. 2000, Tryfonidou et al. 2002). Vitamin D influences the process of mineralization of newly formed osteoid and newly formed cartilage, and thus of endochondral ossification during skeletal growth. It has also been demonstrated that nutritional imbalance during a short period early in life can result in developmental orthopedic diseases (Hazewinkel and Schoenmakers 2006, Tryfonidou et al. 2003). Given that puppies are often fed with milk replacers for several reasons, the aim of the study in Chapter 8 is to identify if the vitamin D concentration in puppy milk replacers (PMRs) is similar to the vitamin D concentration of bitch milk and whether the use of PMR poses a risk factor for orthopedic diseases later in life. One of the common developmental orthopedic diseases in young dogs is medial coronoid disease (MCD). A recently published study demonstrated that MCD is caused by delayed endochondral ossification (Lau et al. 2013, Thompson 2007), which might be due to a (relative) vitamin D deficiency. The aim of the study in Chapter 9 is to identify if supplementation of the daily ration with extra vitamin D during the first growth phase (i.e., 3-18 weeks of age) can prevent development of MCD by stimulating endochondral ossification, including terminal differentiation of chondrocytes, and mineralization of the cartilaginous template of the developing medial coronoid process. In adult dogs with Cushings disease (hyperadrenocorticism) an important source of GH and consequently of IGF-I is suppressed by the negative feedback of cortisol on the pituitary gland. In 85% of the cases of Cushings disease, hyperadrenocorticism is pituitary dependent. Treatment options are either destruction of the adrenal glands, medication to reduce the release of cortisol, or removal of the pituitary gland (e.g. hypophysectomy). The removal of the pituitary gland results in the removal of an important source of GH, and in humans this results in osteoporosis due to decreased 1,25-dihydroxyvitamin D plasma levels and concomitant increased parathyroid hormone (PTH) secretion. The increase of PTH secretion in dogs has been associated with decreased quality of life, appetite, activity, strength, and life span (Nagode et al. 1996). The aim of Chapter 10 is to determine whether in dogs with pituitary dependent hyperadrenocorticism 10 General introduction, aim and scope of the study the PTH-vitamin D axis is disturbed, and whether hypophysectomy leads to lower GH 1 and thus IGF-I blood levels resulting in lowered 1,25-dihydroxyvitamin D synthesis and consequently hyperparathyroidism. The study was to elucidate the necessity of supplementation of vitamin D metabolites to this significant patient group with pituitary dependent hyperadrenocorticism before and/or after hypophysectomy. In human medicine, hypervitaminosis A is associated with liver fibrosis (Castaño et al. 2006), while in cats excessive consumption of vitamin A is thought to cause hyperostosis, mainly located at the cervical vertebrae (Polizopoulou et al. 2005). The mechanisms, by which this hyperostosis develops is still unknown. The role of vitamin A as the sole responsible nutrient was already questioned following a study in which adult cats were fed a diet high in vitamin A for 2 years without demonstrating any effects on the skeleton (Freytag et al. 2003). Notably, the clinical cases describing hyperostosis due to hypervitaminosis A, always involve consumption of raw liver, which contains high amounts of vitamin A and increased levels of vitamin D.