Prognosis and natural history PDB is considered by many to be a benign condition and not ne eding treatment. In some however severe disease can cause deafness, fracture, aggressive ar thritis, and neural spinal compromise. It remains controversial whether pro- phylactic ther apy at an early stage can abrogate or prevent some of these complications. Resources Guidelines See Selby et al. Support groups National Association for the relief of Paget \200\231s Disease: www. paget.o rg.uk; ICD-10 codes M88 M88.0 M88.8/9 Paget \200\231s disease of bone Paget \200\231s disease of skull Paget \200\231s disease of other bones/unspeci \201 ed Figure 14.9 PDB femur (left) showing a number of transverse cortical \201 ssure fractures . PDB tibia (right) with complete mid-shaft fracture. References Langston AL, Ralston SH. Management of Paget \200\231s disease of bone. Treatment Between the mid-1970s and early 1990s the only therapies for PDB available were E tidronate and calcitonin. \200 Rheumatology 2004; 43: 955 \200\2239. Paget J. On a form of chronic in \202 ammation of bones (osteitis defor- The more potent bisphosphonates \200\223 Alendronate, Risedronate, Clodronate, Ibandronate , neridronate, tiludronate, olpadronate, pamidronate and Zoledronate \200\223 have all now shown ef \201 cacy in PDB. The main indication for bisphosphonate treatment is bone pain. Improvement in pain correlates with drop in ALP and other bone turnover markers. Bisphosph onates vary in their ability to produce \200\230remission \200\231 from pain and duration of normalized ALP. Pain may not necessarily be from pagetoid bone, but from osteoarthritis in joints adjacent to pagetoid bone or radicular lesions (e.g. expansion of vertebrae). mans). Trans Med-Chir Soc 1877; 60: 255 \200\22336. Rebel A, Malkani K, Basle M, Bregeon C. Is Paget \200\231s Disease of bone a viral infection? Calcif Tiss Res 1997; 22(Suppl): 283 \200\2236. Scarsbrook a, Brown M, Wilson D. UK guidelines on management of Paget \200\231s disease of bone. Rheumatology 2004; 43: 399 \200\223400. Selby PL. Guidelines for the diagnosis and management of Paget \200\231s disease: a UK perspective. J Bone Miner Res 2006; S2: 92 \200\2233. Siris ES, Roodman GD. Paget \200\231s disease of bone. In: Favus MJ (ed.) Primer on the met abolic bone diseases and disorders of bone min- eral metabolism, 6th edn. Washington DC: AS BMR, 2006; 320 \200\22330. This page intentionally left blank OSTEOMALACIA AND RICKETS 422 Osteomalacia and rickets Osteomalacia (in adults) and rickets (in children) is the consequence of low vitamin-D, cal cium, or phosphorus. The manifestations of the severe condition are bone pain, fractures, m yopathy, and calcium de \201 ciency. In some forms of osteomalacia, phosphate depletion oc curs as part of the primary defect. Mild hypovitaminosis-D is very common, can be associate d with muscle and bone aches (rather than frank myopathy), and results in poor bone mineral ization (osteoporosis) through SHPT. Calcium de \201 ciency may re \202 ect chronically poor dietary intake, gut disease (poor absorption), or excessive calcium excretion. Vitamin D de \201 ciency is common. Studies in places such as Boston, Finland, and Northern Europe show that sub- stantial rates of de \201 ciency occur in different ages and populations. Secondary hyperparathyroidism (SHPT) in these studies is not unusual. Isolated calcium de \201 ciency rickets or osteomalacia i s unusual. Low calcium intake in the infant \200\231s weaning period, diets high in phytate and oxalate. Some tradi- tional African diets particularly can lead to calcium de \201 - ciency rickets age 4 \200\2238 years. Muscle weakness may be less common than in vitamin D de \201 ciency states. Types of osteomalacia and rickets \200 \200 \200 \200 \200 \200 Nutritional de \201 ciency. Drug induced. Pseudovitamin D de \201 ciency rickets. Heredit ary vitamin-D resistance rickets. Hypophosphataemic vitamin D resistant rickets. Tumor-indu ced osteomalacia. Etiology and pathophysiology Osteomalacia and nutritional de \201 ciency rickets can be caused by either vitamin-D or c alcium de \201 ciency or (usu- ally) both. Nutritional phosphate depletion causing osteo- malacia/rickets is unusual given the ubiquitous presence of phosphate in foodstuffs. There are rare hereditary causes of rickets (see below). \200 Vitamin D biology Vitamin D is formed from the effect of UV-B sunlight on 7-dehydrocholeste rol in skin cells. Two forms (D2/ergocal- ciferol and D3/cholecalciferol) are formed. D2 is about 30% as effective as D3 at maintaining vitamin-D status. Both forms bind to vitamin-D binding protein in the blood and are hydroxylated in the liver (to 25-OHD). The pro- ducti on of this (still) inert form of vitamin-D is not tightly regulated and 25-OHD is the most reliable measure of total body vitamin-D status. The active vitamin-D form, 1,25-dihydroxyv itamin D, is generated in the kidney from hydroxylation of 25-OHD. 1,25-dihydroxyvitamin D has a variety of biological actions in tissues, but its known actions are primarily on gut and skeleton. Low vitamin D leads to poor (vitamin-D dependent) cal- cium absorption from the small bowel and SHPT. Low 1,25-dihydroxyvitamin D can aggravate SHPT (reduction of suppression of PTH production). SHPT causes osteopaenia, renal tubular calcium retention, and urinary phosphat e loss, which worsens the osseous lesion. Bone and growth plates become \200\230mineral-po or \200\231. Vitamin D insuf \201 ciency is de \201 ned by consensus as the level below w hich it leads to an elevation of SHPT [essentially around 75 nmol/l (25 g/l)]. In disease due to calcium de \201 ciency, 25-OHD is in the reference interval, but PTH and 1,25-dihy droxyvitamin D are elevated. The latter can lead to early degradation of 25-OHD and lead to vitamin D de \201 ciency. Biological functions of 1,25-dihydoxyvitamin-D \200 Facilitates and enhances calcium (duo denal) and phosphate (entire small intestine) absorption from the gut. Triggers osteoblast RANKL which, through RANK interaction, activates osteoclasts to resorb bone releasing calci um into the circulation. Triggers osteoblast production of a number of media- tors importan t for laying down bone osteoid. Decreases PTH synthesis and secretion. Non-calcaemic action s through genomic vitamin-D response elements (vitamin-D receptors): \200 \200 \200 25 20 15 \200 10 5 effects on many different tissues; broadly anti-proliferative and pro-differentiative; in v ivo consequences not well understood. 0 0 50 100 150 25-OHD (nmol/l) Figure 14.10 The relationship of 25-OHD with PTH in any given Caucasian population: the con cept of vitamin D insuf \201 ciency. Nutritional de \201 ciency Epidemiology \200 Hypovitaminosis-D is prevalent in extreme latitudes, in people who do not expose their skin to sun and is increasingly prevalent with age. Babies excessively breast-fed by mothers wi th dark skin and infants fed only non-dairy milk substitutes are at risk of rickets. As 25-OHD falls below 70 \200\22380 nmol/l, PTH (Y-axis shown in pmol/l) begins to rise. Th us at or below this level 25-OHD might be considered \200\230insuf \201 cient \200\231 to prevent compensa- tory secondary hyperparathyroidism (SHPT). The clinical consequences of \200\230insuf \201 ciency \200\231 are debated. CHAPTER 14 Bone diseases 423 Clinical features Key points in history \200 The commonest \201 nding in osteomalacia is osteopaenia, demonstrated on radiographs or o n DXA scans \200\223 often confused with osteoporosis. Can exist without many symptoms. Bone and muscle pains, however, are common, often non-spec i \201 c, chronic, and widespread. Patients have often been previously misdiagnosed with \201 bromyalgia, chronic fatigue, and depression. Bone pain is often unremitting. Myalgias and weakness in hip and proximal leg musculature is typical. Treatment Vitamin D de \201 ciency There are a number of alternatives for achieving Vitami n D repletion. Increasing UV skin exposure and oily \201 sh con- sumption can be recommen ded if there is insuf \201 ciency alone without bone and muscle disease or underlying path ological association, in the non-elderly. \200 People/populations at risk of osteomalacia \200 \200 \200 In infants and young children Vitamin D drops 5000 \200\22315 000 iu (125 \200\223375 g) daily for 2 months usually corrects de \201 ciency. Normalizing ALP and (rickets) radiogra phic features takes a few months longer. Adolescents and adults can be given daily (10 000 iu/250 g) or weekly (50 000 iu/1.25 mg) ergocalciferol (D2) for several months. If adhere nce with prescribed oral therapy is likely to be an issue, intramuscular ergocalciferol 300 ,000iu every 6 weeks is an alternative. Initial replacement with 1,25-dihydroxyvitamin D is not usually necessary in simple nutritional de \201 ciency but may be sensible if there i s small bowel or liver disease. Calcium correction (and resolution of SHPT) can follow 25-O HD correction automatically unless there is malab- sorption or marked calcium dietary restr iction. Initially calcium replacement can be used (e.g. 25-50mg/ kg/day) especially if diet ary intake is poor. Institutionalized elderly. Elderly with little or no sun exposure. Excessive sunscreen use or sun avoidance (e.g. people with pale, sensitive skin, SLE). All people, particularly dar k-skinned people, living at extreme latitudes. Where ethnicity/religion implies all skin is covered. Chronic liver disease. Previous gastro-duodenal surgery/duodenal pathology. Long- term anticonvulsant use. \200 \200 \200 Key points on examination \200 Full examination is necessary to consider causes of widespread pain including: conditions c haracterized by axial and peripheral enthesitis and osteitis, particularly psoriatic arthri tis/enthesitis, and chronic sarcoidosis, myositis/myopathies and other chronic arthritides. Check gait for myopathic features (waddling, leaning back, slow, slightly wide based, usin g walking aids). Examine for muscle weakness in quads, pelvic stabilizers (Trendelenberg), and shoulder girdle muscles. Tenderness of muscles, bony prominence points, ten- dons and l igaments is usually non-speci \201 c. Patients may satisfy ACR criteria for \201 bromyal gia \200\223 caution! Calcium de \201 ciency \200 1g daily calcium supplements for 6 months is usually suf- \201 cient to correct de \201 ciency unless there is malabsorp- tion or co-existent vitamin D de \201 ciency. Prevention of Hypovitaminosis D and calcium de \201 ciency (and osteomalacia/rickets) \200 There is controversy over the recommended daily intake (RDI) of oral vitamin D and calcium in infants, adoles- cents and adults required to prevent calcium and vitamin D insuf \201 ciency and \200\223 in the long-term given dietary and lifestyle habits \200\223 de \201 ciencies. RDI of calcium varies between 700 and 1500 mg for adults with the highest levels recommended for the elderly and breast-feeding mothers. Investigations Laboratory \200 Bone biochemistry: calcium is usually normal, phosphate may be normal or low, ALP may be no rmal or raised. Urinary calcium excretion usually low. 25-OHD is usually <25 nmol/l (10 g /l) and PTH raised >5 pmol/l, but often much higher. Renal function needs testing because l ow GFR is associ- ated with phosphate retention and high PTH, and this complicates interpre tation of tests. Liver function, folate, iron studies, celiac autoantibodies, autoimmune se rology may all be useful in selected patients to rule out associated conditions or conditio ns causing non-speci \201 c pains mimicking symptomology. Bone biopsy. Rarely needed for u ncomplicated clinical scenario but can be useful if >1 bone disease likely to exist (e.g. o steomalacia and osteoporosis). Main feature: excess unmineralized osteoid (see Plate 30) Calcium-containing food Amount Calcium (mg) Cheese 600 \200\2231000 100 g ( \211\2103 oz) Semi-skimmed milk 1285 1 l ( \211\2101 pints) Yogurt 225 125 g ( \211\2104 oz) Spinach 130 100 g ( \211\2103 oz) Canned sardines in oil 550 100 g ( \211\2103 oz) RDI for vitamin D varies given the reference population. In The USA it is 200 iu (5 g) pe r day for children and adults <50 years and 600 iu daily for those >70 years. In the absenc e of sunlight the RDIs for dietary vitamin D, however, are likely to be inadequate to maint ain vitamin- D repletion. Imaging \200 Features of rickets can develop quickly. Defects occur at growth plates: initially blurring of the growth plate appearance then widening of physes with splaying of the long bone meta physes. Pseudofractures \200\223 small radiolucent lines through bone cortices \200\223 t ypically in femoral neck, pelvis and ribs \200\223 are shown by radiographs and isotope bo ne scintigraphy and are present where osteomalacia is severe OSTEOMALACIA AND RICKETS 424 Drug-induced osteomalacia \200 Hypophosphataemic vitamin D resistant rickets/X-linked hypophosphataemia (XLH) \200 Cholestyramine can reduce vitamin D gut absorption when used in the long-term for binding b ile salts in post- iliectomy diarrhea. Aluminum containing antacids can reduce phosphate ab sorption causing hypophosphataemic osteomalacia. Renal reabsorption of phosphate can be cau sed by cad- mium and ifosfamide. The main causes of drug-induced osteomalacia however are a nticonvulsants. The effect is greatest with (?exclu- sive to) hepatic enzyme inducing agent s: \200 Named as hypophosphataemia vitamin D resistant rickets by Albright in 1937, the most common form of this con- dition is also known as X-linked hypophosphataemia (XLH) \200\223 a dom inant trait. Condition is due to mutations in PHEX gene, which encodes a Phosphate regulati ng gene with homologies to endopeptidases on the X chromosome (Xp22.1-22.2). More than 180 PHEX mutations have been identi \201 ed (www.phexdb.mcgill.ca). PHEX protein primarily reg ulates fibroblast growth factor 23 (FGF-23) levels. It is presumed that mutations in PHEX c an impair enzymatic cleavage (and deactivation) of FGF-23 (and probably other similar prote ins termed \200\230phosphatonins \200\231). FGF-23 has a key role in regulating normal pho sphate homeostasis in a number of tissues. Its levels vary inversely with the expression of Na-P co-transporters at cellular membranes in a variety of tissues. Abnormalities in FGF-2 3 and phosphate homeostasis are gradually being investigated in a number of conditions, par ticularly those involving renal pathology. Some but not all XLH patients do have high FGF-2 3 levels. High FGF-23 may simply be a consequence of a PHEX gene mutation. To date, no FGF- 23 gene mutations have been found in XLH. Presentation is unusual before the child starts t o walk though the condition can often be suspected from a positive family history. An affec ted child develops rickets, lower limb deformi- ties, and is slow to walk. Skeletal growth is slow and dental abnormalities can be severe. Biochemically, there is hypophosphataemia, phosphatu- ria, and functionally low 1,25-dihydroxyvitamin D for the (low) level of serum p hosphate. Serum calcium, PTH, and 25-OHD levels are normal. Treatment is with frequent dail y dosing of phosphate initially 40 mg/kg/day increasing to 100 mg/kg/day, but not to exceed 3 g daily. Raising serum phosphate will cause functional hypocal- caemia and SHPT which wi ll worsen phosphaturia so additional therapeutic (bd) calcitriol is given to suppress PTH ( 25 \200\22375 ng/kg/day). If growth is still poor growth hormone can be considered and some successes are noted. Continuing treatment in adults is somewhat debated. Symptomatic patie nts can derive bene \201 t from continuing therapy. Whether to continue to use calcitriol alone or with phosphate supplements is also debated. The commonest long-term complications of treatment are nephrocalcinosis and hyperparathyroidism. Thiazides may slow the developme nt of the former. Untreated SHPT can result in tertiary hyperparathyroidism for which parat hyroidectomy is the only option. the most frequently implicated drugs are phenytoin and phenobarbitone; phenytoin, and possi bly phenobarbitone, may have direct toxic effects on bone thus contributing to bone fragili ty through causing osteoporosis as well as osteo- malacia; anticonvulsant induced osteomala cia risk is greatest in the institutionalized and in those who avoid sunlight or have poor calcium dietary intake (often the more socially disadvantaged); biochemical abnormalities a re typical though ALP can be raised owing to hepatic enzyme induction from the anti-epileps y drug alone; studies comparing the success of treatment with ergocalciferol (as above), co mpared with therapeutic 1,25-dihydroxyvitamin D (calcitriol) have not been done; issues wit h adherence to oral therapy and a continual need to take anticonvulsants would suggest long -term monitoring for drug-induced osteomalacia in epilepsy patients is prudent. Pseudovitamin D de \201 ciency rickets \200 Autosomal recessive condition caused by mutations in 25-hydroxyvitamin D 1A-hydroxylase gen e. Presents in the \201 rst year of life with rickets, hypocalcae- mic seizures, SHPT, hy pophosphataemia and very low or undetectable levels of 1,25-dihydoxyvitamin D; however, the re is normal circulating 25-OHD. The condition is cured with calcitriol and calcium supplem ents, which need to be continued life-long. Hereditary vitamin D resistant rickets \200 Autosomal recessive condition caused by mutations in vitamin D receptor (VDR). In affected patients mutations in all VDR functional domains have been demonstrated (DNA, ligand, and c o-modulator binding). Often a history of parental consanguinity \200\223 parents typically functionally normal heterozygotes. Presents in infancy with rickets and hypocalcaemia symp - toms \200\223 tetany/seizures, SHPT, hypophosphataemia, tooth enamel hypoplasia, and alo pecia totalis. Distinguished biochemically from pseudovitamin D de \201 - ciency by high 1 ,25-dihydroxyvitamin D and by a poor/ lack of response to calcitriol. In 50% patients there is some VDR function thus thera- peutic response to calcitriol and calcium supplements can be seen. In total VDR function lack therapy with IV calcium can ameliorate the rickets les ions. Sporadic remission can occur after skeletal growth though is not usual. Management of condition through pregnancy and serious intercurrent illness is dif \201 cult. Autosomal dominant hypophosphataemic rickets (ADHR). \200 As in XLH there is a variable age in onset. Like XLH, however, presentation is generally in childhood or in young adults. A family history may be obtained. Clinically ADHR is very si milar to XLH when it presents in infants (see above). CHAPTER 14 Bone diseases 425 ADHR is biochemically indistinguishable from XLH and TIO (see below). Serum FGF-23 levels a re elevated. The defect in ADHR appears to be in the FGF-23 gene. Mutations probably render FGF-23 resistant to (deacti- vating) cleavage, thus lead to excessive levels. As a result there is a decrease in transmembrane phosphate trans- port and generation of 1,25-dihydroxy vitamin D. Treatment is as for XLH. Finding the tumors \200 Imaging with somatostatin receptor and bone scintigra- phy can be useful in identifying tum or location and the extent of osteomalacia lesions respectively. Bone scintig- raphy can di sclose lesions of \201 brous dysplasia, which can hide phosphatonin-producing tumors or a ctivity. Positive 18FDG PET can identify small tumors. Given the frequent disclosure of tum ors in the facial bones/sinuses CT scanning of the sinuses has been sug- gested as a useful \200\230blind \200\231 investigation to arrange. In a high proportion of cases, imaging f ails to initially identify tumors. In such patients treatment (see below) will help, but re peated investigations, sometimes years into the future, can ultimately reveal tumors. \200 Tumor-induced osteomalacia/oncogenic hypophosphataemic osteomalacia A rare acquired conditi on. Osteomalacia bone and muscle disease occurs because of severe hypophosphataemia caused by \200\230phosphatonins \200\231 produced by tumors. Clinical and biochemical characteristics \200 Treatment \200 Presents usually in adults age 40 \200\22360 years with progres- sive, sometimes long-stand ing, myopathy, and bone pain. Often many different diagnoses have been made. Fragility frac tures are common in established disease. Underlying tumors producing the phosphatonin (com- monly FGF-23) are often small, benign and dif \201 cult to detect \200\223 often overloo ked by patient or other doctors. Hypophosphataemia is often profound. There is renal phosph ate wasting and inappropriately low 1,25-dihy- droxyvitamin D for the level of serum phosph ate. Serum calcium, 25-OHD and PTH are usually normal though ALP is invariably raised. Bone histomorphometry shows profound osteomalacia. FGF-23 and other phosphatonins (Secreted Fri zzled Related Protein 4 [sFRP4], Matrix Extracellular Phosphoglycoprotein [MEPE] and Fibrob last Growth Factor 7 ([FGF-7]) cause urine phosphate loss owing to reduced proximal renal t ubule phosphate reabsorption. Resection of tumors cures the condition. Frequently, tumors can \200\231t be found or resec tion is infeasible. TIO is treated with calcitriol 1 \200\2233 g/day and phosphorus (2 g/ day in divided doses). Doses should be tailored to improve symptoms, maintain fasting phosp horus in the reference interval, normalize ALP, and control SHPT without causing hypercalca emia or hypercalciuria. With optimal calcitriol and phosphorus usage the myop- athy and ost eomalacia regresses. Monitoring for nephrocalcinosis and renal dysfunction long-term is nec essary (?hypercalciuria from calcitriol). \200 Resources ICD-10 codes M83 M83.0 \200\2239 Adult osteomalacia Various classi \201 cations of osteomalacia (e.g. M83.2 adult osteomala cia due to malabsorp- tion; M83.5 Other drug-induced osteomalacia in adults) Rickets Vitami n D de \201 ciency, unspeci \201 ed Disorders of phosphorus metabolism (in- cludes vitami n-D-resistant osteomalacia/ rickets) Pathophysiology \200 E55 E55.9 E83.3 Excessive FGF-23 is produced by a tumor. Excessive FGF-23 inhibits renal tubular phosphate reabsorption and down-regulates 25-hydroxyvitamin D 1A-hydroxy- lase enzyme activity in the kidney leading to low 1,25- dihydroxyvitamin D. Gross phosphate wasting occurs and leads t o osteomalacia. Tumors are usually mesenchymal cell rich, often small, benign, slow-growing and located in discrete places. FGF-23 RNA is abundantly expressed in these tumors. TIO ha s been associated with a variety of carcinomas, neuro \201 bromatosis and \201 brous dys plasia of bone also. Gene expression pro \201 les of tumors associated with TIO have sugge sted some other \200\230phosphatonin \200\231 candi- dates including sFRP4, MEPE, and FGF- 7. References Bischoff-Ferrari HA, Dietrich T, Orav EJ, Zhang Y, Karlson EW, and Dawson-Hughes B. Higher 25-hydoxyvitamin D levels are associ- ated with better lower extremity function in active and inactive adults 60+ years of age. Am J Clin Nutr 2004; 80: 752 \200\2238. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vi tamin D status. Osteoporos Int 2005; 16: 713 \200\22316. Holick MF. Evaluation and treatment of disorders of calcium, phos- phorus and magnesium. In : Noble J (ed.) Textbook of Primary Care Medicine, 3rd edn. St Louis: Mosby, 2000; 886 \200 \22398. Differential diagnosis \200 Holick MF, Garabedian M. Vitamin D: photobiology, metabolism, mechanism of action and clini cal applications. In: Favus MJ (ed.) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th edn. Washington DC: ASBMR, 2006; 106 \200\22314. TIO patients often get diagnosed with \201 bromyalgia or chronic fatigue syndrome. As myo pathy and bone lesions develop (and become positive on bone scintigraphy) then TIO can be m istaken for skeletal malignancy). In many reported cases, where correct diagnosis has been delayed, there is often a situation where persistent hypophosphataemia has been overlooked. TIO presenting in infants, children and young adults can appear similar to XLH and ADHR cl inically and identical biochemically. Generally, TIO presents much later in adulthood than XLH or ADHR. Jan de Beur SM. Tumor-induced osteomalacia. J Am Med Ass 2005; 294: 1260 \200\2237. Veith R. Vitamin D supplementation, 25hydroxyvitamin D concen- trations and safety. Am J Clin Nutr 1999; 69: 842 \200\22356. RENAL BONE DISEASE 426 Renal bone disease Chronic kidney disease (CKD) is associated with increased bone fragility and abnormalities of bone turnover tradi- tionally referred to as renal osteodystrophy (ROD). appropriate PTH responses (secondary hyperparathyroidism [SHPT]). When the kidneys can no l onger eliminate more phosphate in response to PTH, phosphate levels rise. Through the effec ts of hyperphosphataemia on PTH production and further suppression of 1A-hydroxylation \200\223 mediated probably through a variety of mechanisms (see Martin et al., 2006) \200 \223 calcitriol is lowered, potentially further aggravating hypocalcaemia. \200 De \201 nitions The US National Kidney Foundation (NKF 2002) classi \201 es CKD on estima ted GFR calculated by the Modi \201 cation of Diet in Renal Disease (MDRD) formula (NKF K/ DOQI). Chronic PTH gland stimulation can eventually cause: \200 \200 Table 14.14 Stages of CKD parathyroid gland nodular hyperplasia; excessive PTH secretion even if hypocalcaemia is cor - rected (often leading to tertiary hyperparathyroidism); calcium and phosphate to be relea sed from bone exacerbating hyperphosphataemia and occasionally leading to hypercalcaemia. CKD stage GFR (ml/min/1.73 m2) 1 >90 Evidence of chronic kidney damage 2 60 \200\22389 Evidence of chronic kidney damage Hyperphosphataemia-induced \201 broblast growth factor 23 (FGF-23) may additionally suppr ess 1A-hydroxylation of 25-OHD. 3 30 \200\22359 4 15 \200\22329 5 <15 End-stage renal disease Clinical features ROD is asymptomatic in the early stage. In advanced dis- ease, bone pain is prominent particularly in OF. Focal skel- etal pain may be due to microfractures. The as sessment can be complicated by the presence of other musculoskel- etal lesions associated w ith CKD. The abnormalities of the skeleton in CKD are collec- tively known as renal osteodystrophy ( ROD). ROD has recently been de \201 ned as an alteration of bone morphology in patients wi th CKD. ROD is associated with a 3 \200\2234 \227 in- crease in fractures and is a complex disorder of compro- mised bone strength consisting of a spectrum of skeletal abnormalities. Co-morbidities SHPT and vascular disease \200 High PTH >600 pg/ml (63 pmol/l), calcium >2.37 mmol/l and phosphorus (>1.6 mmol/l) are asso ciated with an elevated risk of death and cardiovascular events. Arterial calci \201 catio n either occurs in the intimal layer within atherosclerotic plaques or affects the tunica m edia causing medial wall calci \201 cation. The latter increases vascular stiffness, reduc es vascular compliance, elevates systolic blood pressure, widens pulse pressure, and causes left ventricular hypertrophy. Skeletal abnormalities in renal osteodystrophy (ROD) Bone and bone mineral abnormalities \200 \200 \200 \200 Osteitis \201 brosa and mild hyperparathyroidism. Osteomalacia. Vitamin D related. Non vi tamin D related: Chronic metabolic acidosis; alu- minium accumulation. Phosphate depletion. Adynamic bone disease (low bone turnover). Mixed uraemic osteodystrophy. Amyloid bone dise ase. Osteoporosis. \200 \200 \200 \200 CKD and osteoporosis. WHO grades of BMD are not ideally used to diagnose osteoporosis or in dicate fracture risk in CKD4/5 patients with GFR <30 ml/min or on dialysis because: \200 WHO BMD grades only apply to healthy Caucasian post-menopausal women. All forms of ROD may be associated with low BMD. How ROD subtypes relate to T-scores and fracture risk is unknow n. Aortic calci \201 cation may lead to misleading elevation of measured BMD of the spine on the AP projection. Patients with end-stage renal disease have other risk fac- tors for b one fragility: heparin and glucocorticoid (GC) use, hypogonadism, poor nutrition, 25-hydrox yvitamin D (25-OHD) de \201 ciency and metabolic acidosis. Epidemiology The prevalence of ROD in end-stage renal disease (ESRD) can vary with dialysis modality. The frequencies of the main forms of ROD de \201 ned histologically in patients undergoing peritoneal dialysis (PD) are: \200 \200 \200 \200 \200 Osteitis \201 brosa (OF) <10%. Adynamic bone disease (ADB) 60%. Mixed (OF+ADB) <10%. Oste omalacia. In those having haemodialysis, OF is about 4 \227 more CKD and musculoskeletal conditions Gout, calcium pyrophosphate dihydrate disease, and other arthropathies due to calcium and phosphate containing crystals can occur in advanced CKD p atients. Secondary tendonopathies and mechanical joint failure can ensue. The incidence of osteonecrosis and septic arthritis is elevated in CKD compared with controls. prevalent, but ADB about half as frequent as in PD. ROD may complicate osteoporosis: 50 \200\22370% of elderly women presenting with hip fractu res (mean age 84 years) have a GFR <35 ml/min. Etiology and pathophysiology As GFR declines there is impaired excretion of phosphate and r eabsorption of calcium and decreased renal 1A- hydroxylation of 25-OHD to calcitriol, despi te initial CHAPTER 14 Bone diseases 427 Investigations Laboratory Measurable PTH correlates with the predominant histo- logical abn ormality in bone. High iPTH levels suggest oste- itis \201 brosa and low iPTH re \202 ec ts low bone turnover ROD. But overlap is common. Management of osteoporosis in ROD \200 Oral bisphosphonates and strontium ranelate are prob- ably safe in CKD 3, but cautioned in CKD 4 and 5. There are no fracture end-point studies for any therapy in CKD 4 and 5 patient s. Management of ROD post-transplant Fracture risk post-transplant is 4 \227 that of the norma l population and chie \202 y relates to glucocorticoid use and is managed best in light of renal function. \200 Secondary causes of osteoporosis may need excluding (e.g. 9 a.m. testosterone and LH in men) Imaging Radiographs, DXA, and other techniques measuring BMD cannot predict ROD subtype wit h accuracy. \200 Tertiary PTH+, present pretransplant and can resolve spontaneously, but take years to do so . Replace 25-OHD insuf \201 ciency/de \201 ciency. Consider calcimimetics or parathyroide ctomy if: \200 \200 \200 \200 Rule out hypogonadism in men. Stop smoking, reduce al cohol, increase weight-bearing exercise, and minimize doses of GCs. In those with fractures and high PTH oral bisphosphonate therapy would seem a logical choice, but no fracture outc ome studies have been done. \200 BMD data may not be a useful clinical tool in predicting fracture. Studies are lacking. Bon e scintigraphy can highlight the distribution of OF. Patterns correlating to ADB are not we ll recognized. PTH-induced hypercalcaemia persists; hyperparathyroidism is severe; there is severe bone fr agility (fractures); there is severe joint disease (e.g. CPPDD) Histology: bone biopsy The diagnosis of ROD essentially requires a bone biopsy. \200 \200 Bone biopsies are reported using three histological descriptions \200\223 bone turnover, m ineralization, and volume. Bone biopsies are used rarely in many centers perhaps owing to t he number of pathologists skilled in the detailed analysis of bone tissue. ROD features on undecalci \201 ed bone biopsy Acknowledgements With thanks to Dr Brian Camilleri, Consultant Nephrolo- gist, for his impo rtant contribution on the text. ROD subtype Histomorphometry/features Osteitis \201 brosa High bone turnover Markedly increased remodeling activity Resources Guidelines For physicians, guidelines on managing renal bone disease and other Adynamic bone disease Low bone turnover Decreased remodeling activity and osteoid surfaces aspects of CKD are at www.renal.org. Osteomalacia Low bone turnover Decreased remodeling activity Increased osteoid surfaces ICD-10 codes N25.0 Renal osteodystrophy N25.8 SHPT of renal origin Mixed Patchy areas of osteitis \201 brosa Increased osteoid References Cunningham J, Sprague S. Osteoporosis in chronic kidney disease. Am J Kidney Dis 2004; 43: 566 \200\22371. Treatment Osteoporosis risk in patients with CKD 1 or 2 and early CKD 3 should be managed r outinely. EBPG Expert Group on Renal Transplantation. European best prac- tice guidelines for renal t ransplantation. Section IV: long-term management of the transplant recipient. Bone disease. Nephrol Dial Transplant 2002; 17(Suppl 4): 43 \200\2238. Management of metabolic abnormalities in CKD3 \200 Elder G. Pathophysiology and recent advances in renal osteodys- When GFR is <60 ml/min iPTH should be measured and if elevated 25-OHD checked (NKF, 2002). 25-OHD de \201 ciency is common and is a risk for severe hyperparathyroidism in CKD. If 25 -OHD is insuf \201 cient (<75 nmol/l), supplemental vitamin-D3 and calcium can be given wi th advice to increase skin exposure to the sun. 25-OHD de \201 ciency (<25 nmol/l) is ofte n associated with osteomalacia bone and muscle lesions, and high dose 25-OHD repletion then may be needed. trophy. J Bone Min Res 2002; 17: 2094 \200\22315 Martin KJ, Ziyad Al-A, Gonzalez EA. Renal osteodystrophy. In: Favus MJ (ed.) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th edn. Washington DC: ASBMR, 2006:359 \200\22366. Moe S, Dreuke T, Cunningham J, et al. De \201 nition, evaluation, and classi \201 cation of renal osteodystrophy: a position statement from kidney disease: improving global outcome s (KDIGO). Kidney Int 2006; 69: 1945 \200\22353. NKF. National Kidney Foundation K/DOQI clinical practice guide- lines for chronic kidney di sease: evaluation, classi \201 cation, and strati \201 cation. Am J Kidney Dis 2002; 39(S uppl 2): S1 \200\223246. Ramsey-Goldman R, Dunn JE, Dunlop DD, et al. Increased risk of fracture in patients receivi ng solid organ transplants. J Bone Miner Res 1999; 14: 456 \200\22363. Management of SHPT in ROD In CKD 4 and 5 key components of management are to: \200 Reduce phosphate retention by restricting dietary phos- phate, using frequent dialysis and phosphate binders (e.g. sevalamer). Optimize PTH levels by judicious use of active vitamin- D analogs (e.g. 1A-calcidol, calcitriol or paricalcitol). Consider calcimimetics (e.g. Cina calcet), which increase the sensitivity of the PTH gland calcium-sensing recep- tor thereby reducing PTH release. OSTEOGENESIS IMPERFECTA 428 Osteogenesis imperfecta Osteogenesis imperfecta (OI) is a rare autosomal domi- nant inherited disorder of connectiv e tissue characterized by bone fragility and fracture. Forms are chie \202 y due to abnormalities in Type 1 collagen and clinically varied \200\223 from a lethal phenotype an d mild forms that may only manifest as osteoporosis in adults. Classi \201 cation of OI by type OI type Clinical features Inheritance I Normal stature. Little or no deformity. Blue sclerae. Hearing loss in 50% AD II Lethal in the perinatal period AD III Progressive deformity. Short stature. Sclerae vary. DI common. Hearing loss common AD/AR (rare) IV Mild to moderate bone deformity. Variable short stature. DI common. Occasional hearing loss . Sclerae vary. AD AD, gene unknown V Phenotypically the same as IV but also triad of hypertrophic callus formation, dense metaph yseal bands, interosseous membrane ossi \201 cation. Normal Type 1 collagen Phenotypically the same as IV. iALP. Fish scale appearance of bone under microscope Phenotypically the sa me as IV. Found only in small Quebecois community. Blue sclerae. Rhizomelia. Moderate to se vere bone disease. VI Unknown VII AR, gene at 3p22-24.1 AD=autosomal dominant; AR=autosomal recessive; DI=dentinogenesis imperfecta. Classi \201 cation Broadly in keeping with general features associated with recognized phe notypes there are varying degrees of growth de \201 ciency, dentinogenesis imperfecta, hea ring loss, macrocephaly, blue sclerae, scoliosis, barrel chest, and hypermobility. OI is co nventionally described according to Sillence. \200 Some features are common to all OI types: \202 at mid-face, bluish sclerae, yellow or opa lescent teeth, relative macro- cephaly, barrel chest and pectus excavatum, joint laxity. Type I OI \200 Mildest form of OI. Fractures occur postnatally often when child starts to mobilize, but in cidence of fracture decrease after puberty. Occasionally, presents in early middle age as \200\230early osteoporosis \200\231. Hearing loss can occur \200\223 often late in childho od or early adulthood. Growth de \201 ciency, long bone deformity, and dentino- genesis im perfecta are unusual. Sillence described 4 types according to clinical features. Three further types have been ad ded though these have been described on the basis of additional non-clinical parameters. Ty pes IV \200\223VI appear to have normal type 1 collagen. Epidemiology OI is rare. Reliable \201 gures of prevalence and incidence don \200\231t ex ist. Both males and females are affected. Cases, families, and disease clusters in small et hnically restricted groups have been described from across the world. Type II OI \200 Generally lethal in the peri-natal period. Birth often premature and are small for gestatio nal age. There are major skeletal deformities and demise usually follows respiratory insuf \201 ciency. Type III OI \200 Etiology and pathophysiology \200 >90% of OI patients have abnormalities in type 1 collagen. Types V \200\223VI do not have t ype 1 collagen mutations. Type 1 OI is due to reduced synthesis of structurally normal type 1 collagen and have an increase in type 3: type 1 collagen ratio. In types II \200\223IV a mixture of normal and abnormal collagen is synthesized. With rare exceptions the structura l defects are either glycine substitutions or an in-frame deletion from alternate exon spli cing. Defects in collagen chains impair helix folding and expose chains to enzymes for long er thus chains become excessively modi \201 ed. Recessive forms of OI are probably caused by parenteral mosaicism for a dominantly inherited mutation. Severe type with progressive deformity. Fractures occur very commonly. Bones deform from no rmal muscle ten- sion. Extreme growth de \201 ciency and scoliosis common. Type III is com patible with full life span, although respira- tory insuf \201 ciency and cor pulmonale ca n occur in middle age. Respiratory problems frequently complicate and com- promise long-ter m health. \200 Type IV OI \200 Moderately severe. Diagnosis can be at birth although often not until becomes mobile or eve n starts school. Typically several fractures a year occur though decrease after puberty. Fi nal stature is small and children may be responsive to growth hormone. Compatible with norm al life-span. Radiographically, there is osteoporosis and many develop scoliosis and verteb ral fractures. Clinical features OI can present at different ages thus its differential diagno- sis varies dependently (see below). A positive family history is absent because mutations occur de no vo. CHAPTER 14 Bone diseases 429