Therapies \200 \200 \200 \200 Glucocorticoids Cyclosporin Methotrexate Anticonvulsants Other \200 \200 \200 \200 \200 \200 \200 \200 Anorexia nervosa. Juvenile idiopathic arthritides. Cancer \200\223 notably leukemia. Immob ilization owing to neurological disease. Thalassaemia. Cystic \201 brosis. Gaucher diseas e. Organ transplant. Etiology and pathophysiology Low bone mass and fractures \200 IJO \200 \200 In healthy children there may be interactions between the factors determining growth and su sceptibility to fracture. These effects may be most relevant when growth velocity is greate st. In these healthy children an integration of further factors such as activities and trau ma risk, calcium and/or vitamin D status and genetic in \202 uences [e.g. allelic variatio n in the lipoprotein receptor-related protein 5 (LRP5)] might be important in conferring a de \201 cit in load-adaptational skeletal integrity. Pathophysiology is unknown. Bone biopsies from IJO children show reduced activa- tion frequ ency, and low remodeling activity and osteob- last function. No increased bone resorption h as been detected. The poor bone formation may be selective being con \201 ned to bone surf aces exposed to bone mar- row. Intracortical and periosteal surfaces are less affected than trabecular-rich bone areas. No underlying genetic abnormality has been consistently report ed. Secondary osteoporosis \200 Other forms of primary osteoporosis \200 Immobilization is a contributory cause to bone loss associated with many chronic diseases p articularly neu- rological diseases. The presumed mechanism is lack of bone formation as a result of suboptimal mechanical stimulation of bone. Chronic in \202 ammation underscores bone loss or poor formation in Crohn \200\231s disease, juvenile idiopathic arthritis (JIA) and cystic \201 brosis (CF), identi \201 able before any GC therapy is started. Ulcerat ive colitis probably isn \200\231t associ- ated with secondary osteoporosis. Osteoporosis r isk is greatest where multiple risk factors exist. For example, systemic in \202 ammation, liver disease and relative immobility will all likely contribute to bone loss in CF; low b ody and muscle mass, poor estrogen Though a condition caused by defective bone collagen formation, OI is considered to mimic c hildhood oste- oporosis. It is almost universally associated with child- hood bone fragilit y (see p. 428). The heritable conditions of connective tissue Ehlers \200\223 Danlos syndro me, Bruck syndrome, Marfan syndrome, homcystinuria and osteoporosis pseudoglioma syn- drome are all rare causes of primary osteoporosis. Clinical features \200 Children and adolescents with osteoporosis are likely to present either with fractures alon e, or secondary to systemic disease, or with typical features of IJO. CHAPTER 14 Bone diseases 413 Differential diagnosis \200 Any assessment should include the appraisal of underly- ing diseases, which is beyond the s cope of this chapter. Calcium intake is dif \201 cult to assess formally, but a cur- sory review of dietary habits might throw light on poor nutritional status. IJO classically pres ents with an insidious onset of pain in the back, hips, and feet with dif \201 culty walki ng. Pain can involve extremities. Muscles may be weak. Fractures in IJO typically occur at bone metaphyses. Some recommend IJO be diagnosed only when there are vertebral compression fractures present. The distinction of recurrent fractures with low bone mass in healthy children compared with secondary oste- oporosis requires exclusion of systemic disease. IJO may need distinction from OI in certain children, notably those presenting with fractures <10 years old. Multipl e fractures in infancy may be due to non-accidental injury/child abuse. Table 14.11 The differential diagnosis of IJO and OI IJO OI Investigations Laboratory tests \200 Familial No Often Tests are aimed at characterizing the presence and activ- ity of the condition causing the osteoporosis. Measuring vitamin D (25-OHD), parathyroid hormone (PTH), and routine bone bio chemistry may be prudent whatever the likely cause of osteoporosis as calcium and vitamin-D de \201 ciency can complicate any other cause of poor bone health, and would be easily co rrectable with supplements in most cases. Onset Late prepubertal Birth or soon after Fractures Metaphyseal; incl. vertebral Long bone diaphyseal Growth rate Normal Normal or low Connective tissues No involvement Hypermobility, blue sclerae, Bone biopsy \206\223Bone turnover \206\221Bone turnover; hyperosteocytosis Radiographs and dual X-ray absorptiometry (DXA) \200 Major fractures of the spine are simply detected by lat- eral spinal radiographs. Subtle ve rtebral fractures are not easily detected though algorithms for detecting rela- tive verteb ral height loss are being investigated. Careful radiological assessment of long bone appear - ances may be necessary where the differential diagnosis lies between OI and IJO. In IJO s mall radiolucent bands at sites of newly-formed metaphyseal bone are typical. DXA measureme nts are strongly in \202 uenced by changes in bone and body size related to age and pubert al devel- opment. BMD estimated from a measure of bone min- eral content in a 2D area of gr owing bone is dif \201 cult to normalize for given the variety in growth rates for age in healthy children, but notably where growth deviates excessively from the mean \200\223 a s ituation more frequently encountered in association with pathology. The factors above are a mpli \201 ed for the hip and forearm compared with the spine. The comparison of a BMD meas ure with its reference range should be interpreted carefully. Different BMD correction algo rithms have been proposed. One of the simplest divides bone mineral content (BMC) by the 3D volume of the bone calculated from the measured verte- bral area and assuming the vertebra is a cube. This is called the bone mineral apparent density (BMAD). Genetics LRP5 mutations in some Collagen type 1 in most patients Treatment \200 Where there is no secondary osteoporosis, and both IJO and OI have been excluded, then advi ce regarding trauma risk should be given, but patients and their fami- lies reassured. Alth ough calcium supplementation has led to convincing increases in BMD in healthy children in the short-term, the long-term advantages are unproved. Studies of weight-bearing activity h ave been generally positive in terms of improving BMD. Adherence in the long-term, however, has proved a problem In all forms of osteoporosis, bisphosphonates are the treatment of ch oice, and should be given with additional calcium and vitamin D supplements. In secondary o steoporosis, robust long-term fracture end-point studies are lacking, but bisphosphonates a re tolerated well for up to 3 years. Calcium supplements, usually with vitamin D should be considered in children with osteoporosis and chronic liver disease, those with fractures an d low dietary calcium intakes, and those on anticonvulsants. Key points regarding diagnosis of osteoporosis in children \200 \200 \200 Resources See under Post-menopausal osteoporosis The diagnosis should not be made on DXA results alone. DXA should be done only in specialis t centers. Z-scores, ideally of the LSp, should be quoted, not T-scores, and compared with the best available refer- ence interval data. The value of BMD to predict fractures has not yet been determined Age-related Z-scores are unreliable in children who are small for thei r age A variety of algorithms may help correct for bone size, growth variation and pubertal development. There is no consensus on which method to use Whole body BMC and quantitative Computerized Tomography (QCT) may offer advantages over hip and LSp BMD. Corrections may st ill need to be made for BMC and radiation doses are relatively high for QCT References Adams J, Shaw N, on behalf of the Bone Density Forum. A Practical Guide to Bone Densitometry in Children. Bath: National Osteoporosis Society 2004. Available at: ww.nos.or g.uk Bianchi ML. Osteoporosis in children and adolescents. Bone 2007; 41: 486 \200\22395. Manias K, McCabe D, Bishop N. Fractures and recurrent fractures in children: varying effect s of environmental factors as well as bone size and mass. Bone 2006; 39: 652 \200\2237. Ward L, Tricco A, Phuong P, et al. Bisphosphonate therapy for chil- dren and adolescents wi th secondary osteoporosis. Cochrane Database Syst Rev 2007; 17(4): CD005324. Writing Group for the ISCD Position Development Conference. Position statement: executive s ummary. J Clin Densitom 2004; 7: 7 \200\22312. PRIMARY HYPERPARATHYROIDISM 414 Primary hyperparathyroidism Primary hyperparathyroidism (PHPT) and malignancy ac- count for >90% of all hypercalcaemic patients. PHPT is a hypercalcaemic state resulting from excessive secretion of PTH from one or more parathyroid glands. Although his- torically patients may have presented with marke d neuro- myopathic, or cardiac features, or even pancreatitis, PHPT is usually detected ear ly in its course now and rarely pres- ents with such severe clinical manifestations. Peptic ulcer disease is unlikely to be related to PHPT unless as part of a MEN syndrome. Se vere pancreatitis is thought to be unusual nowadays. The association of PHPT with hypertens ion (and thus cardiac and renal disease) is debated. It may be that vas- cular calci \201 cation accounts for an increased risk of such disease in the long-term. Bone pain due to PH PT bone disease (osteitis \201 brosa cystica) is likely to be rare nowadays. Radiographic rep- resentation of it (regardless of symptoms) may be seen in <5% of PHPT cases in the US A for example. Epidemiology \200 Benign PHPT is relatively common with an incidence of between 1:500 to 1:1000. A 4 \200\223 5 \227 increase in PHPT incidence was noted in the early 1970s because of the widespread us e of the labora- tory auto-analyzer and the disclosure of hypercalcaemia in patients being tested for other problems. Women are affected more than men 3:1. PHPT can rarely be part of familial multiple endocrine neoplasia (MEN 1 or 2a). MEN1 has an estimated prevalence of 2 \200\2233/100 000 and typically PHPT associated with MEN1 presents by the age of 50 years. MEN2a is rarer. Table 14.12 Familial hyperparathyroid syndromes Heritable predisposition to tumors MEN1 Parathyroid adenomas (PHPT), anterior pituitary and adrenocortical adenomas, pancreatic isl et tumors, duodenal gastrinomas, bronchial or thymic carcinoids, lipomas, facial angio \201 bromas, truncal collagenomas. \200 MEN2a Medullary thyroid cancer, phaeochromocytomas, multiglandular PHPT. Co-morbidities Renal disease Patients with PHPT should be screened for hypercalciuria (see below) and renal calci \201 cation. Renal disease should be an important factor in decidin g timing for parathyroidec- tomy and should be monitored for closely in conserva- tively ma naged PHPT patients. Etiology and pathophysiology \200 PHPT is caused by a single benign solitary adenoma in 80% of cases. Four-gland hyperplasia is seen in 15 \200\22320%. MEN1 may account for around 2% of PHPT cases. PHPT due to carcin oma is rare (<0.5% of PHPT cases). There is loss of normal feedback control of PTH by extra cellular calcium. Why precisely the control is lost at a molecular level is unknown. There is no change in calcium sensitivity of individual parathyroid cells ( \200\230set point \200\231) in PHPT due to adenomas. Excess PTH relates to parathyroid cell number. Underlyin g genetic causes postulated to be relevant in some cases of PHPT include: gene rearrangemen ts lead- ing to altered growth potential of parathyroid cells; over- expression of cyclin D 1 a cell cycle regulator, loss of a copy of a MEN1 tumor suppressor gene. Both MEN1 and MEN 2a are autosomal dominant condi- tions affecting men and women equally. MEN1 occurs seconda ry to a mutation of the MEN1 tumor suppressor gene (11q13). The gene encodes the protein \200\230menin \200\231 whose gene regulatory functions have not been fully elucidated. Tumo r growth depends on (somatic) acquired mutations occurring in the normal gene copy in one c ell. Thus, a critical check in clonal pro- liferation is removed for that cell MEN2a is due to a mutation in the RET proto-oncogene (chromosome 10) seen in >95% of MEN2a families. RE T is a receptor tyrosine kinase. \200 Arthritis Pseudogout is well recognized as a complication of PHPT. Pseudogout is just one f orm of CPPDD disease, however. The prevalence and impact of CPPDD disease in PHPT has been poorly evaluated. Caution in ascribing arthritis in PHPT patients to osteoarthritis alone i s unwise until a skel- etal survey reviewed by a musculoskeletal radiologist has shown an a bsence of erosive CPPDD disease/arthritis. MEN1 \200 PHPT is the commonest and (typically) earliest manifes- tation of MEN1. Gastric hyperacidit y symptoms in PHPT should raise awareness of the co-existence of a gastrinoma. Familial PHP T without a familial history of any other tumor does not rule out MEN1. Long-term surveilla nce of family members is not unreasonable. MEN2a PHPT is of low penetrance in MEN2a (20% cases). Overall, the commonest tumor is medul lary thyroid cancer (calci- tonin producing), which occurs in >90%. Clinical features \200 Investigations Laboratory \200 Patients are often asymptomatic or present non-speci \201 c symptoms, such as fatigue, a s ense of weakness, intellec- tual weariness. A family history of hypercalcaemia or endocrine tumors raises the possibility of MEN1 and MEN2a. Although theoretically possible, symptoms from hyper- calcaemia and hypercalciuria \200\223 excessive thirst, urinary frequency, no cturia, muscular and bone aches, and abdominal symptoms \200\223 are not always volunteere d. The combination of hypercalcaemia and raised PTH are diagnostic. Phosphate tends to be low or low-normal. PHPT can be associated with normocalcaemia Urinary calcium excretion is elev ated in 35 \200\22340%. 1,25-dihydroxyvitamin D levels are high in about 25% cases (PTH sti mulates 1A-hydroxylase). 25-OHD is often in the insuf \201 ciency range. It is important t o assess renal function, estimating GFR. \200 \200 CHAPTER 14 Bone diseases 415 The NIH guidelines (1990) for managing PHPT have been widely criticized and a consensus has addressed outdated aspects of the guidelines (Bilezikian 2002). Surgery requires exception al skill and experience. Options include a minimally invasive approach under local or gener al anesthetic, useful in removing a single adenoma identified on pre-operative scans or nec k exploration under general anesthetic. In multiglandular disease, all parathyroid gland ti ssue is removed except for a remnant, which is left in situ or transplanted in the non-domi nant forearm. Post-operative complications include prolonged ( \200\230hun- gry bone syndro me \200\231) or permanent (total gland removal) hypocalcaemia and recurrent laryngeal nerve palsy. In MEN1 it is especially important to consider when to operate as adenomas can re-o ccur and multiple opera- tions may be needed in the future. A total neck explora- tion is n ecessary as multiple adenomas can be present and all glands need to be visualized In MEN2a, because undiagnosed phaeochromocytoma can cause death or substantial morbidity at operatio n, it is important to screen for phaeochromocytoma before undertaking parathyroid surgery. Imaging \200 The majority of patients lack radiological manifestations. Osteitis Fibrosa (OF) can occur rarely in advanced PHPT and is manifest by sub-periosteal resorption of distal phalanges, t apering of distal clavicles, patchy ( \200\230salt and pepper pot \200\231) lucencies in of the skull, bone cysts and brown tumors of long bones. Dual X-ray absorptiometry (DXA) can show how PHPT causes a selective resorption of cortical compared with trabecular bone. Disp roportionately low forearm bone mineral density (BMD) compared with LSp may indicate a sele ctive cortical bone-erosive process of PTH. The changes also occur in SHPT. In patients wit h OF, bone scintigraphy can show the extent of the bone disease. Imaging to show any nephro calcinosis/nephrolithiasis is important. The results in \202 uence management decisions. A fter a decision has been made to consider surgery then imaging to locate any parathyroid gl and adenomata is done. Though there is controversy over whether imag- ing is necessary in p atients who have not previously had neck surgery, many would advocate both neck ultra- soun d and 99mTc-sestimibi scintigraphy. The combination of scan results increases the accuracy of abnormal gland location over a single scan. Medical \200 Asymptomatic PHPT patients can do well managed con- servatively. Laboratory measures of bio chemistry and BMD can remain stable for many years. However there are a number of caveats t o the above: \200 25% of patients will have progression of hypercalcae- mia or a decline in BMD over 10 years ; the increase in fracture risk, and determinants of it, in medically-managed PHPT are not well known; patients <50 years have high risk of progressive PHPT; the effect of CPPDD dise ase on quality of life, disabil- ity and joint pain/failure in monitored compared with surg ically treated PHPT is unknown. specialist clinical, laboratory, and BMD monitoring long-te rm is required. \200 PHPT patients should avoid thiazides, may bene \201 t from a regular bisphosphonate avoid calcium supplements and should adopt a low calcium intake diet. Monitoring of renal functio n is required. To reduce effects of hypercalcaemia and hypercalciuria, patients should be a dvised to avoid prolonged immobility and ensure adequate hydration. Calcimimetics play a ro le in medical management by altering the \200\230setpoint \200\231 of the calcium sensing receptor. A biological effect has been demonstrated in the short term (normalizing serum ca lcium for up to 3 years). Figure 14.7 99mTc-MDP scintigraphy in PHPT bone disease (OF): increased tracer/bone turnove r in cranial bones and both humeral and femoral bone metaphyses Treatment Surgical \200 Resources Internet sites www.endocrine.niddk.nih.gov/pubs/hyper/hyper. Surgical removal of the adenoma or hyperplastic par- athyroid gland(s) cures PHPT. The main factors determining a decision to operate are: the presence of signi \201 cant bone or re nal disease, if the patient is young or has marked hypercalcaemia. There is, despite guidel ines, still considerable contro- versy when to operate in asymptomatic individuals. Some ev idence suggests surgery improves quality of life and BMD measures compared with conservativ e man- agement for asymptomatic PHPT. htm www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=en docrin&part=A742; (Review of PTH and vitamin -D biol- ogy/pathol.) ICD-10 codes E21.0 Primary hyperparathyroidsim PRIMARY HYPERPARATHYROIDISM 416 References Arnold A. Familial hyperparathyroid syndromes. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th edn. Washington: ASBMR, 2006; 185-8. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. The natural history of treated a nd untreated asymptomatic primary hyper- parathyroidism: a ten year prospective study. N En gl J Med 1999; 41: 1249 \200\22355. Silverberg SJ, Bilezikan JP. The diagnosis and management of asymp- tomatic primary hyperpa rathyroidism. Nat Clin Pract Endocrinol Metab 2006; 2(9): 494 \200\223503. Arnold A, Shattuck TM, et al. Molecular pathogenesis of PHPT. J Bone Miner Res 2002; 17: N30 \200\2236. Bilezikian JP, Potts JT, et al. Summary statement from a workshop on asymptomatic PHPT: a p erspective for the 21st century. J Bone Miner Res 2002; 17 S2: N2 \200\22311. This page intentionally left blank PAGET \200\231S DISEASE OF BONE (OSTEODYSTROPHIA DEFORMANS) 418 Paget \200\231s disease of bone (osteodystrophia deformans) Described originally (but inaccurately) as an \200\230osteitis \200\231 (oste- itis deform ans) in 1877 by Sir James Paget (1814 \200\22399), this condition, named after him, is most accurately, but perhaps not most \200\230catchily \200\231, referred to as osteodystrophi a deformans. Paget \200\231s Disease of bone (PDB) is a localized disease of bone remodelin g. Structural changes in bone, notably expansion, occur as a result of increases in disorde red osteoclast func- tion. The site and severity of skeletal involvement varies considerabl y and many patients are asymptomatic. PDB has a variety of long-term consequences on joint and nerve function primarily as a result of local expansion of affected bone. PDB can be cl assi \201 ed as symptomatic (bone pain) or asymptomatic and described by its local effect (e.g. deform- ing, secondary arthritis) and also its extent: \200 \200 However, genetic in \202 uences alone are unlikely to account for PDB given the focal (not complete skeletal) nature of the condition. Environment \200 For >30 years studies have suggested PDB may be caused by a paramyxoviral infection. Origin ally, nuclear and cytoplasmic inclusions were described in PBD bone, which were thought to resemble paramyxoviral nucleocapsids. Subsequently, measles, canine distemper, and respirat ory syncytial virus have been linked with PDB from a variety of studies using immunocytoche mistry staining of PDB sections for nucleocapsid proteins and in situ hybridiza- tion of vi ral nucleocapsid transcripts in affected bone. Theories linking paramyxoviral infection wit h PDB have been weakened by the failure of some researchers to reproduce the results publis hed by others. Some cogent arguments weaken the case for a viral aeti- ology alone. For exa mple, if viruses are ubiquitous and found globaly, why is PDB not found globaly? Also, how do viruses persist for decades in immunocompetant people assuming most are contracted in ch ildhood but PDB occurs in the elderly? Monostotic: one bone or portion of bone affected. Polyostotic: 2 or more bones affected. Epidemiology \200 Occurs in both men and women and is commonly diag- nosed in the elderly. It is rare to make the diagnosis in adults <25 years and thought to occur primarily after 40 years. Ethnic an d geographical clustering occurs. PDB is com- mon in Europe, N America, Australia, and NZ. PDB has been described in East European, and Sub- Saharan African and Arabic populations, b ut the preva- lence rates are very low. In both North and South America, rates are higher i n people of European descent compared with indigenous groups and those with Afro- Caribbean origin. Prevalence in Europe is 0.5 \200\2234.5% and 3 \200\2234% in Australia and NZ. Rat es decrease from north to south in Europe. In Lancashire, UK 6 \200\2238% people >55 years have PDB. Recent studies point to a decline in PDB prevalence \200\223 cause unknown. Pathology \200 The hallmark is increase in bone resorption from multi- nucleate osteoclasts and increased osteoblasts. Increased bone turnover is shown by increases in serum and urinary resorption markers (e.g. deoxypyridinolene, type 1 collagen N- and C- telopeptides). Coupled osteoblas t activity increases and is re \202 ected in increases in ALP. In early PDB increased oste oclast activity predominates with lytic lesions ( \200\230blade of grass \200\231 lesion in long bones). New bone formation is coupled but accelerated and col- lagen \201 bres are laid down haphazardly. Ultimately, there is a mosaic pattern of woven bone. Bone marrow is in \201 ltrated by excessive \201 brous connec- tive tissue and blood vessels. Bone matr ix is normally mineralized \200 Etiology and pathophysiology Genetic \200 PDB commonly occurs in families: there is an AD pattern of inheritance, 1st degree relative s of an affected person are 7 \227 more likely to get PDB. Several genetic loci have been l inked to familial PDB: \200 Clinical features Key features in history \200 Predisposition loci have been detected on chromo- some 18 and 6. No speci \201 c genes ide nti \201 ed. A mutation in a gene (5q35) encoding an ubiquitin binding protein, sequestoso me-1 (SQSTM14/p62ZIP), has been detected in 11/24 French-Canadian families with PDB. The main symptom is bone pain. It often remains at rest and is deep seated. The commonest b ones affected are pelvis, femurs, vertebrae, skull, and tibiae. Typical features in the his tory (though non-speci \201 c) from skull involvement include: deafness (skull PDB affecti ng VIIIth cranial nerve neural canal or inner ear bone func- tion); change in shape of head /increase in hat size; neck/ occipital pain or intrinsic headache; dental/gum prob- lems (m andible involvement); change in timbre of voice (from changes in nasal bone shape and narro wing of the airway). Groin/anterior thigh pain might suggest hip OA second- ary to pelvic o r femur PDB. Symptoms of spinal claudication might suggest lumbar vertebral PDB (see also P late 24). There is current focus on a number of genes, which affect NF-kB signaling (e.g. data from P DB families and studies, which link PDB extent/severity to severity of mutation). SQSTM1 is a \200\230scaffold protein \200\231 important in the NF- B activation pathway. SQSTM1 mu tations probably rele- vant to PDB cluster at its C-terminus (ubiquitin-binding domain). Ho wever, direct evidence for a functional effect of SQSTM1 mutations in vivo is thin. If rele vant to PDB pathophysiology, the SQSTM1-NF- B signaling pathway may be abnormally complica ted by factors, which affect the correct assembly and function of the multi-protein signali ng complex (Apkc-SQSTM1- traf6). Thus, other genetic in \202 uences affecting this path- w ay may clearly be relevant in determining the heterogeneity of PDB. Key features on examination \200 Look for skeletal deformity (e.g. bowing of femur or tibia, enlarged head for body size/squ are head, widening of gap between teeth, kyphosis). CHAPTER 14 Bone diseases 419 Heat felt over suspected involved bones might represent hypervascularity of Pagetoid bone. Examination needs to be comprehensive and aimed at evaluating possible effects of expanded Pagetoid bone. Referral on to other specialties may be needed. Bowing of legs is associated with leg length discrepancy and mechanically-induced lower back and leg symptoms. Typical patterns of abnormality are well recognized. Polyostotic PDB is easily de \201 ned . Abnormalities point to foci of involvement for further clinical and radiographic assessme nt if necessary. Table 14.13 Examination of a patient with PDB Complication of PDB Examination Platybasia Neurological: rule out myelopathy Spinal canal encroachment Neurological: to rule out spinal canal or radicular nerve exit foramen stenosis Osteoarthritis Rheumatological: to assess hip, knee, and shoulder (typically) Hearing loss Detailed ENT examination Mandibular involvement Maxillofacial examination and oral health assessment Long bone deformities Rheumatological/biomechanical to assess deformity, mobility and assess need for orthoses/mo bility aids Hyper-vascularity Cardiac examination to assess any high output cardiac failure Co-morbidities \200 Hypercalcaemia and hypercalciuria associated with pro- longed immobility. Secondary hyperpa rathyroidism typically seen in those patients with very high ALP levels. Mechanism unknown, but thought to be secondary to low serum calcium in patients requiring high calcium \202 ux into active pagetoid bone. One possible result is associated (mainly periph- eral bone fragility/osteoporosis). Sarcoma is a recognized but very rare complication of PDB. Intense and worsening pain in known PDB site needs investigation for sarcomatous change. Hyperuric aemia and gout. May be a consequence of increased cellular turnover in bone. Other co-morbi dities occur primarily as a consequence of expansion of bone \200\223 see above. Figure 14.8 99mTc-MDP scintigraphy (posterior whole body view) showing PDB in contiguous lu mbar spine vertebrae, right hemipelvis, and skull. Scan also shows osteoarthritic knees CT and MR CT is the imaging of choice where a fracture is not reliably disclosed on plain r adiographs (e.g. \201 ssure fracture of femur). MRI may be considered for: \200 Investigations Laboratory \200 Characterizing radicular nerve root compression or spi- nal canal stenosis. Evaluating any myelopathy at axial (e.g. associated with platybasia) or subaxial spinal levels. Characteri zing the range of lesions at joints affected by adjacent bone PDB. To assess any sarcomatou s change or investigate poten- tial bone metastases within pagetoid bone. Raised ALP. Raised resorption markers (e.g. urinary NTX or serum CTX). Always check blood c alcium and phosphate and 25-hydroxyvitamin-D and PTH (see above). Imaging Radiographs. \200 \200 Appearances are pathognomonic. Bones are typically expanded, show cortical thickening, coar sened trabeculae, and a mixture of lytic and sclerotic areas. Histology/histomorphometry. Bone biopsy is rarely required for a diagnosis of PDB. \200 Cortical and trabecular bone area/volume is greatly increased. Within bone there is a mosai c appearance of packets of both woven and lamellar bone. Wide irregular trabeculae and poor ly de \201 ned junction between trabecular and cortical bone. Scintigraphy. 99mTc-MDP isotope bone scans are the most sensitive way of detecting involved skeletal sites in PDB. PAGET \200\231S DISEASE OF BONE (OSTEODYSTROPHIA DEFORMANS) 420 Though there are many long-term effects from untreated PDB (e.g. deafness, platybasia, cord compression, joint disease, \201 ssure fractures, sarcoma, spinal stenosis), no studies convincingly show that bisphosphonates or other therapy, prevents these effects. All bispho sphonate regimes can cause hypocalcaemia, thus correction of vitamin D de \201 ciency and regular cal- cium supplementation in PDB patients undergoing treat- ment courses is importa nt. Various regimes for giving pamidronate have proved effective. The most commonly used re gimes use 60 \200\22390 mg (in 500 ml 0.9% saline or 5% dextrose) 2 \200\2233 doses given 1 \200\2232 weeks apart. Normalizing ALP with pamidronate in PDB patients prior to orthopedi c operations reduces the amount of blood loss at the operation site. Calcitonin \200\223 w ell established though modestly effective therapy given by SC injection 100 units/day. Ther apy over 3 \200\2236 months associated with reduction in bone pain in a majority and ALP in 50%. Remaining in biochemical remission after cessation of therapy is unusual and in some inde \201 nite treatment might be needed. Escape from therapy (calcitonin receptor down-re gulation or anti- bodies to the drug) is recognized. Flushing, nausea, and headaches are co mmon and can be severe. Osteoclast number may be 10 \227 normal with the cells >100 m wide containing 20 \200\223 100 nuclei. These multinu- cleate osteoclasts are unique to PDB. Osteoblasts are numerous, plump and cuboidal. Osteoid area is moderately excessive and mineral appo- sition rate acce lerated. Peritrabecular and marrow \201 brosis is prevalent near osteoclasts and marrow b lood vessels prominent. Hemorrhage may be noted. \200 Differential diagnosis Malignancy, severe osteomalacia and \201 brogenesis imper- fecta o ssium (FIO) are the main alternatives. \200 FIO is often associated with a paraprotein and has dis- tinct radiographic appearances with out bone expansion or cortical thickening, and characteristically disordered bone collagen appearances on bone biopsy. In some cases, the discrimination of PDB and malignancy will re quire MR characterization of bone and associated soft-tissue lesions though Distinctive pat terns of abnormal 99mTc-MDP scintigraphy, carefully interpreted, discriminates pathology. 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.