CALCIUM PYROPHOSPHATE DIHYDRATE DISEASE 388 Calcium pyrophosphate dihydrate disease De \201 nition Calcium pyrophosphate disease (CPPDD) deposition in joints results in both an acute and chronic arthropathy. The term pseudogout is used to describe the acute arthrit is caused by CPPDD crystals. Chondrocalcinosis is the name used to describe the radiologica l appearances of crystal deposition within cartilage, but is not speci \201 c for CPPDD cr ystals and can occur with deposition of other minerals. is unclear. How crystals reach a joint, cause in \202 ammation, and how resolution of an a cute attack occurs are also poorly understood. As with gout, a number of precipitants of an acute attack are recognized, which include intercurrent illness, stroke, trauma, surgery, and some drugs. Clinical presentation Key features in history and examination Acute pseudgout (Type A) \200 \200 History CPPDD crystals were \201 rst identi \201 ed in 1962, but the patho- physiology o f crystal formation and disease progression is poorly understood. Treatment is therefore sy mptomatic. This is the commonest presentation of pseudogout. The term pseudogout re \202 ects the cli nical similarities between an acute attack of CPPDD and gout. A monoarticular presentation is typical. Pain is acute in onset with pain, swelling, and erythema. The knee, wrist, shou lder, and elbow are the commonest joints affected. Attacks are usually self-limiting, but t end to be more prolonged than gout. Fever with malaise may occur. Precipitants of an attack include intercurrent illness preceding the onset of an attack, trauma, and surgery. Elderl y patients can present with systemic malaise, with hypotension and confusion, mimicking sys temic sepsis or other conditions. \200 \200 Diagnostic criteria Demonstration of the presence of CPPDD crystals on po- larized light mi croscopy is the gold standard diagnostic test. Classi \201 cation Rosenthal and Ryan proposed diagnostic criteria for CPPDD disease in 20 01 and, although useful, does not allow classi \201 cation of all patients. A different cl assi \201 cation is based on de \201 ning sporadic, familial and secondary causes. \200 Table 13.2 Rosethal and Ryan diagnostic criteria for CPPDD disease Pseudorheumatoid presentation (type B) \200 Type A Pseudogout/acute in \202 ammatory monoarthritis Large joint symptoms are common, with history of generalized stiffness. Small joint involve ment is rare. Early morning stiffness may be marked. Differentiation from rheumatoid arthri tis may be dif \201 - cult, but CPPDD is not associated with rheumatoid fac- tor, CPPDD cr ystals are isolated from the joints and \202 ares of CPPDD typically affect one joint at a time, whereas in rheumatoid arthritis \202 ares are more general- ized. Type B Pseudorheumatoid/polyarthritis with synovitis \200 \200 Type C &D Pseudo-osteoarthritis/joint degeneration with (type C) or without (type D) acute synovitic attacks Type E Asymptomatic (incidence unknown) Type F Pseudoneurotrophic/severe joint destruction with or without neuropathy Others Tophaceous CPPDD deposits, spinal CPPDD deposits, crowned dens syndrome, spinal stenosis Pseudo-osteoarthritis (Types C and D) \200 Epidemiology \200 Pain and stiffness is the commonest presentation of the pseudo-osteoarthritis types. Examin ation reveals a restricted range of movement. The pattern of joint involvement may be usefu l as upper limb involvement may occur, a pattern less commonly seen in patients with osteoa rthritis. Type C has acute \202 ares of pseudogout on the back- ground of pseudo-osteoart hritis. Treatment of type D is as for osteoarthritis. Prevalence and incidence have been dif \201 cult to deter- mine in view of the broad spect rum of presentation, but an estimation of prevalence suggests CPPDD to be between half that or equivalent to gout. CPPDD is more prevalent in women, with an average age at presentati on of 72. Both incidence and prevalence increase with age, with presentation unusual below the age of 50 years. The presence of CPPDD in patients less than this age should prompt inv estigation of underlying metabolic causes. Radiographic prevalence is estimated to be 8.1%, rising to 27.1% in those over 85. Familial CPPDD appears to be a heterogenous group of dis eases mostly inherited by an autosomal dominant inheritance and associated with severe, pre mature CPPDD disease. \200 Asymptomatic (Type E) \200 These patients are picked up incidentally on plain radiographs. This may reflect the larges t group of patients with CPPDD disease. Neuropathic CPPDD disease (Type F) This is rare, but describes those cases where CPPDD dis- ease has been described in the presence of neuropathy in association with tertiary syphili s. Etiology and pathophysiology It remains unclear why patients develop CPPDD crystals, althou gh abnormalities in pyrophosphate metabolism seem to be central. Crystal deposition in cart ilage appears to result, with deposition in both hyaline and \201 brocartilage. Histologi cally, large chondrocytes can be identi \201 ed, which are not found in osteoarthritis, al though the role of these Other forms of CPPDD disease Tophaceous deposits of CPPDD, similar to those seen in tophace ous gout are rare. They are described in tendons, bursae, and bone. CHAPTER 13 Crystal arthritis 389 Chondrocalcinosis re \202 ects CPPDD/mineral deposition within both hyaline and \201 bro cartilage The commonest areas to \201 nd chondrocalcinosis include the medial and lateral menisci of the knee, the triangular \201 brocartilage of the wrist, and the symphysis pu bis. Eburnation, joint space narrowing and subchondral cysts, but with a relative paucity o f osteophytes are typical. A destructive arthropathy in joints rarely affected by oste- oar thritis may raise the possibility of CPPDD disease. Spinal disease, such as disc calci \201 cation and subchondral cysts occur in the facet joints. Spinal deposits occur in the ligametum \202 avum, resulting in clinical symptoms of cord compression, in either the cervical or lumbar spine. The crowned dens syndrome describes acute attacks of neck pain due to CPPDD deposition arou nd the atlanto- axial joint, and may be associated with fever and malaise. Natural history Unlike gout, there is no established progression from one type of CPPDD dis ease to another, although type D would be reclassi \201 ed as type C following an acute ep isode of pseudogout. Co-morbidities There are a number of conditions which are thought to be associated with CPP DD. Screening for these is important if CPPDD disease is diagnosed in anyone under the age of 50. \200 \200 \200 \200 \200 \200 Haemochromatosis. Hypothyroidism. Wilson \200\231s disease. Hyperparathroidism. Hypomagnesa emia. Hypophosphataemia. Other looser associations include gout, sustained hypercal- caemia, and diabetes mellitus. Investigations in acute pseudogout Blood tests \200 A mild to moderate leucocytosis is seen in acute attacks. The in \202 ammatory response is re \202 ected in elevation of acute phase proteins including CRP and ESR. Serum creatinin e to establish baseline renal function prior to treatment should be established. Blood cult ures will be negative, but should be collected if septic arthritis is a possibility. Blood tests are unhelpful in chronic CPPDD disease. Screening of younger patients for underlying metabolic associations should include calcium, magnesium, and ferritin. Figure 13.1 This plain radiograph was requested as the patient complained of hip pain, but incidental symphyseal chondrocalcinosis was evident. Differential diagnosis Septic arthritis is the most important diagnosis to exclude, because of its associated mortality and morbidity. Other crystal arthropathies may result in simil ar clinical features. \200 Joint aspiration and synovial \202 uid analysis \200 Joint aspiration and synovial \202 uid analysis is the most important diagnostic test. Sy novial \202 uid is frequently heavily blood stained. Synovial \202 uid should be cultur ed even if CPPDD crystals are identi \201 ed as crystal arthropathy and sepsis can co-exis t. CPPDD crystals are weakly positively birefringent rhom- boid-shaped crystals under polar ized light and are more dif \201 cult to identify than monosodium urate crystals. Crystals may deteriorate in synovial \202 uid so refrigeration should be considered if analysis i s delayed. Crystals may be dif \201 cult to identify, and microscopy can therefore be nega tive. Crystals can be intra- or extracel- lular, making identi \201 cation in synovial \202 uid more dif \201 cult. There is no correlation between the severity of an acute atta ck and the number of crystals found in the synovial \202 uid. \200 Imaging \200 Plain radiographs may be normal and, therefore, unhelpful in acute pseudogout, although the presence of chondro- calcinosis does make the diagnosis more likely. Soft tissue swelling may be seen, but is a non-speci \201 c \201 nding. Figure 13.2 This plain radiograph of the knee shows dense tricompartmental chondrocalcinosi s with early osteoarthritis. Chondrocalcinosis was detected within the symphysis pubis on a plain radiograph in this patient with osteoarthritis of the hip. CALCIUM PYROPHOSPHATE DIHYDRATE DISEASE 390 Treatment Aim of treatment during the acute episode \200 \200 \200 Internet sites http://www.library.nhs.uk/musculoskeletal/ ViewResource.aspx?resID=77860 Exclude septic arthritis. Pain relief with NSAIDs and simple analgesia. Intra-articular inj ection of glucocorticoid has been shown to reduce the duration of attacks of acute pseu- do gout, although no randomized controlled trials exist. Treat any underlying precipitating ca use. Rest the joint. www.patient.co.uk/showdoc/40001166/ Controversies There are no targeted therapies in CPPDD disease be- cause current understand ing of the pathophysiology re- mains to be established. \200 There is no evidence base for the role of oral glucocorti- coid therapy in patients with re current attacks of pseudogout. In patients with severe destructive arthropathy, there are n o randomized controlled data to demonstrate a disease modifying effect of any therapeutic a gent. Aim of treatment during recurrent attacks/chronic CPPDD \200 Low dose colchicine (1 mg/da y) may reduce the frequency of attacks. Low dose oral prednisolone is sometimes used in pat ients with frequent attacks, but there is no evidence base to support this. Patients with p seudorheumatoid CPPDD may respond to DMARD therapy, and success has been reported with gold and hydroxychloroquine. Joint replacement surgery may be necessary for those joints in whi ch there is extensive cartilage loss. ICD-10 codes M11 M11.1 M11.2 Other crystal arthropathies Familial chondrocalcinosis Other chondrocalcinosis References Bouvet J, et al. Acute neck pain due to calci \201 cations surrounding the odon toid process: the crowned dens syndrome. Arthritis Rheum 1985: 22: 928 \200\22332. Prognosis The natural history remains unclear in long-term disease. Doherty M, Dieppe PA, Watt I. Pyrophosphate arthropathy: a propsepctive study. Br J Rheumatol 1993; 32: 189 \200\22396 Kohn NN, Hughes RE, McCarty DJ, et al. The signi \201 cance of calcium pyrophosphate cryst als in the synovial \202 uid of arthritis patients: The \200\230pseudogout syndrome \200 \231. II. Identi \201 cation of crystals. Ann Intern Med 1962; 56: 738 \200\22345. Patient advice \200 No lifestyle changes have been shown to alter the frequency of attacks. The joint should be rested in the event of an acute attack. Patients should be advised to seek medical attenti on in the event of a new attack in order to exclude other causes of hot swollen joint and t o speed the administration of intra-articular glucocorticoid therapy to terminate an acute attack quickly. Reginato AJ, Tamesis E, Netter P. Familial and clinical aspects of calcium pyrophosphate de position disease. Curr Rheumatol Rep 1999; 1: 112 \200\22320. Rosenthal AK. Pathogenesis of calcium pyrophosphate crystal deposition disease. Curr Rheumatol Rep 2001; 3: 17 \200\22323. Rosenthal AK, Ryan LM. Calcium pyrophosphate crystal deposition disease; pseudogout; articu lar chondrocalcinosis. In: Koopman WJ (eds) Arthritis and Allied Conditions, 14th edn. Phil adelphia: Lea and Febiger, 2348 \200\22371. Resources Guidelines There are no accepted guidelines for the management and treatment of C PPDD disease. This page intentionally left blank THE BASIC CALCIUM PHOSPHATE CRYSTALS 392 The basic calcium phosphate crystals De \201 nition The deposition of calcium containing crystals in joints or soft tissue surr ounding joints causes localized pain, swelling and tenderness in the majority of patients. The crystals implicated in this process include those formed from calcium pyrophosphate dih ydrate and basic calcium phos- phate (BCP) crystals, which include carbonated-substituted h ydroxyapatite, tricalcium phosphate, and octacalcium phosphate. BCP will be discussed here. examination con \201 rms swelling and tenderness of the affected area. Calci \201 cation can be asymptomatic and picked up on incidental radiological investigations. The site of in volvement may be unusual, for example, toes, wrists, elbows, and ankles. Joint involvement results in a destructive arthropathy, for example, the Milwaukee shoulder. Symptoms are usu ally self-limiting. Classi \201 cation and spectrum of disease There are no classi \201 cation criteria, but a number of clinical conditions are recognized and include: \200 \200 \200 \200 Presentation of commonly involved joints Milwaukee shoulder \200 The classical presentation is in elderly women with rapidly accumulating shoulder effusions . Symptoms and disease are unresponsive to glucocorti- coid injections or other treatment m odalities. Joint disease results in underlying joint destruction and is often associated wi th a large rotator cuff tear. Calci \201 c tendinitis/acute periarthritis of the joint capsule. Crystal associated osteo arthritis. Acute synovitis of small joints. Destructive arthropathy, e.g. Milwaukee shoulde r syndrome. Monoarticular presentation is the commonest presenta- tion, although occasional ly polyarticular disease may occur. The shoulder is the commonest joint involved and may oc cur bilaterally. Other less common sites include the elbow, wrist, hand, knee, ankle, foot, and spine. Elbow Calci \201 cation can occur in the tendons, bursae, and the joint capsule. Hand and wrist The commonest site of tendon involvement in the hand and wrist is in the \202 exor carpi ulnaris tendon. Diagnostic criteria \200 The identi \201 cation of calcium containing crystals within the affected joint is diagnos tic, although the crystals are small and not detected on routine microscopy with polarized light. Definitive diagnosis requires electron microscopy although alizarin red S stain and polarized light micros- copy has been used as a basic screening test. No accepted diagnosti c criteria have been developed, but the presence of typical clinical features and the prese nce of calci \201 cation on radiological investigations make the diagnosis probable. Hip and pelvis Tendinous calci \201 cation can occur in gluteus medius and minimus (around the greater and lesser trochanters of the hip). Knee The quadriceps and patellar tendons may be affected as may the bursae and the joint ca psule. Ankle and foot The Achilles tendon may be affected along with a number of other different t endons and ligaments. Epidemiology \200 Spine Paraspinal ligaments may develop calci \201 cation, with the longus coli tendon the most commonly affected. Most cases occur in patients aged between 30 and 50, although BCP has been described in chi ldren. Men and women are equally affected. Calcium containing crystals are reported in up t o 60% of patients undergoing knee arthroplasty due to the association with osteoarthritis. \200 Natural history Acute calci \201 c tendinitis is usually self-limiting, but destruc- tive arthropathy in joints can be resistant to treatment and tends to be progressive. Etiology and pathophysiology \200 \200 Investigations Blood tests In the majority of cases, normal in \202 ammatory markers and a normal white cell count are found. However, an acute in \202 ammatory response may be see n in patients with acute calci \201 c deposits. The mechanism remains poorly understood. Extra-articular inorganic pyrophosphate is recogni zed as an important factor in the control of calcium crystal formation with high production by chondrocytes implicated in BCP crystal formation. Age and genetic factors are thought t o increase extra-articular inorganic pyrophosphate Imaging \200 The typical appearance on plain imaging is of calci \201 c deposits, which may vary in siz e. These deposits may be unfragmented when found in asymtomatic joints but typically become fragmented in patients with acutely painful joints and an active in \202 ammatory compone nt. Radiographic appearances are of resolution of calci \201 c material if radiographs are repeated. Erosion or breaching of the cortex of the bone may occur and CT is useful in exc luding malignant causes of bone erosion. Risk factors A number of predisposing factors, such as family history, trauma, and degenera tive factors have been postulated, but remain tenuous. Clinical features Key features \200 Pain usually arises from the periarticular tissues with patients describing acute onset of pain, and CHAPTER 13 Crystal arthritis 393 Acute calci \201 c tendinitis is treated symptomatically with NSAIDS, local glucocorticoid injections and physical therapies such as heat/cold compresses, and exercise. More speci \201 c therapies include needling the calci \201 c deposits under ultrasound control, shoc k wave therapy and surgical removal, although the evidence base for these procedures remain s primarily anecdotal. Arthroplasty is occasionally required in severe joint destruction. Patient advice \200 \200 There is no speci \201 c advice to avoid \202 ares of disease. Advice should include res ting the in \202 amed joint and seeking medical advice to exclude other causes of acute jo int pain. Treatment is limited in its success in treating destructive arthropathy. There ar e no recognized triggers for acute attacks. Calci \201 c tendinitis may recur in different locations, but is usually self-limiting. \200 Figure 13.3 On US, calcium deposition can be visualized within the supraspinatus tendon, sh own here by the arrows. Resources Guidelines There are no guidelines for the treatment of basic calcium phosphate c rystal disease. Imaging of affected joints reveals osteoporosis, joint destruction and periarticular calci \201 cation. Histology Macroscopically, a cheesy calci \201 ed material is found in the periarticular s oft tissues. ICD-10 codes M11.0 Hydroxyapatite deposition disease Differential diagnosis The differential diagnosis includes those causes of acute localized pain: \200 \200 \200 \200 \200 \200 \200 References Bonavita JA, Dalinka MK, Schumacher HR Jr. Hydroxyapatite deposition disease. Radiology 1980; 134: 621 \200\2235. Dieppe PA, Huskisson EC, Crocker P, et al. Apatite deposition Septic arthritis Other acute crystal arthropathy AVN Acute tendon tears/tendinopathy Trauma In \202 ammatory arthritis, e.g. RA Other causes of extra-articular calci \201 cation, e .g. meta- bolic disease, or collagen vascular disease disease. A new arthropathy. Lancet 1976; 1: 266 \200\2238. Garcia GM, McCord GC, Kumar R. Hydroxyapatite crystal deposition disease. Semin Musculoskel Radiol 2003; 7: 187 \200\22393. Halverson PB, McCarty DJ, Cheung HS, et al. Milwaukee shou lder syndrome: eleven additional cases with involvement of the knee in seven (basic calcium phosphate crystal deposition disease. Semin Arthritis Rheum 1984; 14: 36 \200\22344. Paul H, Reginato AJ, Schumacher HR. Alizarin red S staining as a screening test to detect c alcium compounds in synovial \202 uid. Arthritis Rheum 1983; 26: 191 \200\223200. Aims of treatment \200 The management of crystal associated osteoarthritis is the same as that for uncomplicated o steoarthritis as no speci \201 c treatment options are available. This page intentionally left blank 395 Chapter 14 Bone diseases Post-menopausal osteoporosis 396 Therapeutics of post-menopausal osteoporosis 402 Osteoporo sis in men 406 Glucocorticoid induced osteoporosis (GIO) 408 Osteoporosis in children 412 P rimary hyperparathyroidism 414 Paget \200\231s disease of bone (osteodystrophia deformans) 418 Osteomalacia and rickets 422 Renal bone disease 426 Osteogenesis imperfecta 428 Miscell aneous bone diseases 1 432 Miscellaneous bone diseases 2 434 POST-MENOPAUSAL OSTEOPOROSIS 396 Post-menopausal osteoporosis De \201 nition Osteoporosis is a disease characterized by low bone mass and/or poor bone q uality, leading to enhanced bone fragil- ity and a consequent increase in fracture risk. Lo w bone mass as measured by bone mineral density (BMD) is one of the most important predispo sing factors for osteoporotic fracture; however, osteoporosis is more than low BMD. It is a disease of compromised bone strength. The determinants of bone strength are: mass, geometr y, and microstructure, material properties, and bone turnover. X-ray absorptiometry (DXA). See Table 14.1. This is an accepted de \201 nition. However, t his is somewhat arbitrary and based on a surrogate, not true, measure of bone den- sity. Cu rrently, direct measures of the other parameters of bone strength are not incorporated eith er into an accepted de \201 nition of PMO or its diagnosis; however, some determinants of \200\230strength \200\231 would be encompassed by a de \201 nition of PMO, which includes bone fragility. Thus, a more comprehensive de \201 nition of PMO might be fracture sustained with low or no trauma (fragility) in association with osteoporotic range BMD (as de \201 ned by The WHO criteria). De \201 nition utilizing a measure of BMD BMD changes with age, increasing to a peak in th e third decade then changing little over a period of consolidation. BMD then decreases slow ly with a usual accelerated phase of bone loss shortly after the menopause. Epidemiology There is an increased incidence of osteoporotic fractures in women with advancing age re \202 ecting deteriorating bone quality and mass, and an increasing tendency to fall. See Fi gure 14.2. Attainment of peak Bone mass Consolidation Age related bone loss Table 14.1 The WHO de \201 nition of PMO BMD Men Menopause T-score Interpretation Women \200\230Osteoporosis \200\231 \200\223 the BMD is at least 2.5 SDs below the peak mean BM D T \211 \200\2232.5 0 10 20 30 40 50 60 70 Age (years) \200\230Osteopaenia \200\231 \200\223 the BMD is 1 \200\2232.5 SDs below the peak mean BM D T > \200\2232.5, but \211 \200\2231.0 Figure 14.1 Changes in bone mass over time. \200\230Normal \200\231 \200\223 the BMD is less than 1 SD below the peak mean BMD T > \200\2231.0 Post-menopausal osteoporosis (PMO) has been de \201 ned by the World Health Organization ( WHO) as a low BMD (see below), ideally measured by hip or lumbar spine dual WHO de \201 nition of PMO based on multiples of the SD of the range of women \200\231s pea k BMD ( \200\230about age 25 \200\22335 years). Men Women 400 400 = Hip fracture = Radiographic vertebral fracture = Wrist fracture 300 300 r a e y / 0 0 0 0 1 200 200 , r e p e c n e d c n 100 100 i I 0 0 50-54 60-64 70-74 80-84 50-54 60-64 70-74 80-84 Age group Age group Figure 14.2 Incidence of fractures. CHAPTER 14 Bone diseases 397 Racial variation in fracture incidence exists with lower rates in Afro-Caribbean compared w ith Caucasian and Asian populations. Environmental factors such as dietary protein intake, vitamin D (25-OHD) status, and genetic factors (see below) are all likely to in \202 uence the gradient of fracture risk within any given population. The commonest sites of fracture associated with bone fragility are: spine, hip, distal forearm, proximal humerus, and pelv is. Consequences of fracture \200 There are about 35 m women estimated to have/have had an osteoporotic fracture worldwide. D isability quan- ti \201 ed as Disability Adjusted Life Years (DALYs), which incorporates m ortality, was recently estimated to be greater for osteoporosis overall compared with cance r with the exception of lung cancer. 50% of those ambulatory prior to hip fracture are unab le to walk independently after. One consequence of having a hip fracture is the need for pe rmanent nursing home care <15% of women 50 \200\22355 years old, but >50% of women >90 year s old. Given the projected increases in life expectancy it has been estimated that fracture s in both women and men will increase from around 1.7m in 1990 to 6.3 m in 2050. Based on t he above and other trends in hip fracture inci- dence, hip fracture is expected to rise fro m 46 000 in 1985 to 117 000 in 2016. Hip fractures \200 Hip fractures are associated with 10 \200\22320% mortality in the \201 rst year after fra cture and substantial morbidity particularly decreasing independence in the elderly. Worldw ide it was estimated there were 1.2 m hip frac- tures in women in 1990. Rates of hip fractu re worldwide increase with increasing latitude. In Western countries, above 50 years old th ere is a female:male ratio of hip fracture of 2:1. A lower rate of hip fracture incidence i n some develop- ing countries re \202 ects the lower life expectancy. Etiology and pathophysiology Genetics There is a signi \201 cant heritable component to BM D, par- ticularly peak BMD, bone turnover markers, and bone geo- metric parameters, each of which has been linked to frac- ture risk. It is estimated that 60 \200\22380% of the varia tion in peak BMD may be due to genetic factors. \200 Vertebral fracture \200 The recent development of morphometric and semi- quantitative measures of vertebral fractur e has facilitated some recent reliable studies of vertebral fracture. Only one-third of spi nal fractures come to medical attention; only 25% follow a fall. Prevalence varies between 12 and 25% in post-menopau- sal women. Rates can vary owing to the dif \201 culty in dis- criminating vertebral deformities from fracture \200\223 often dif \201 cult where fractu re may lead to very minor changes in vertebral height. Prevalence increases with age and th e gradient is steeper in women compared with men. Recent data from the EPIDOS study suggest s fracture prevalence of 19% aged 75 \200\22379 years, 21% aged 80 \200\22384 years, and 41 % in women aged 85 years and older. In Rochester, Minnesota the incidence was estimated as 18% per 1000 women over the age of 50 years. Fractures have an heritable component, shown in 3 large studies from the USA, Sweden, and a n International Study (data from Europe, Canada, and Australia). Polymorphic markers in the vitamin-D receptor gene, in the promotor region of the collagen IA1 (COL1A1) gene (Sp1) an d in BMP2 (chromosome 20p12) have been linked to fracture risk in certain populations. Poly morphisms in the low-density lipoprotein receptor- related protein 5 (LRP5) have been linke d to signi \201 cant variations in BMD. As yet, studies have not consistently linked singl e gene polymorphisms to fracture and fracture risk in different populations. Distal forearm fracture \200 Environment Both exercise and nutritional factors have a role in deter- mining peak bone de nsity (a strong determinant of future PMO) and fracture risk. \200 The incidence of wrist and distal forearm fractures increases after the menopause, although the gradient of increase with age is less steep notably after the age of 75 years compared with hip and vertebral fractures. Distal forearm fracture may be less frequently a conse- quence of a fall with advanced age given fall mechanics. Owing neuromuscular deterioration in the very elderly, a fall forwards onto an outstretched hand is less frequent compared wi th at a younger age. Falls tend to be more sideways or backwards with age, often causing tr auma to the pelvis and posterior femur area. Fracture incidence rises from a premenopausal rate of 10 per 10 000 population/year to 120 per 10 000 popula- tion/year after the age of 85 years. There is a winter peak in presentation. Overall, there is a 4:1 ratio in favor of women compared with men. Weight-bearing exercise increases bone mass by 1 \200\2232%/ year in adolescence. Exercise may also optimize skeletal growth and shape, structural aspects of skeletal growth, which m ay ultimately in \202 uence bone fragility. The type and extent of weight-bearing exercise neces- sary to optimize maintenance of bone mass and/or pre- vent increased bone turnover in post-menopausal women is unknown. Some is better than none! Nutrition: calcium Adequate calcium intake is important for optimal skeletal growth and gai n in bone mass in children and adolescents, and maintenance of bone mass and reduction of a bnor- mally increased bone turnover in the elderly. \200 Fracture is a risk for fracture \200 Calcium intakes are positively correlated with bone mass at all stages of life. Western die ts typically high in protein and salt, and low in potassium can increase urinary calcium lo ss. Recommended daily intakes of calcium vary with age and skeletal development, and in the context of the country \200\231s/ region \200\231s typical dietary constituents (Table 14. 2). Generally, the presence of one fragility fracture increases the risk of further fractures i f no anti-osteoporosis treat- ment is given. Predictive power of further fracture is probab ly greatest for vertebral and hip fracture. Distal forearm fracture predicts an excess risk of fracture after 70 years old. POST-MENOPAUSAL OSTEOPOROSIS 398 Calcium de \201 ciency is most accurately determined by an elevation in PTH assuming there are no other reasons for PTH elevation. Calcium de \201 ciency is usually a conse- quence of vitamin D de \201 ciency, the two co-exist invari- ably to varying degrees. The rate of age-dependent skeletal deterioration (e.g. loss of trabecular connectivity) is more likely a function of environmental compared with genetic in \202 uences. Risk factors Risk factors can be considered to be intrinsic or environ- mental, mostly a consequence of lifestyle. Two major risks for PMO, low BMD, and falls, are in \202 uenced in turn by a co mbination of both intrinsic and environmental components. Table 14.2 Recommended calcium intakes Age group or person Calcium intakes recommended by different authorities US National Institute of Health UK Dept., of Health* Table 14.3 PMO: main risks for fracture Infants and children From 270 mg at 7 \200\22312 months to 1300 mg age 12 years 350 \200\223550 mg Intrinsic Environmental/lifestyle Age Low body weight Teenagers 1300 mg 800 \200\2231000 mg Caucasian/Asian race Cigarette smoking Women 1000 mg (1200 mg in women >51 years) 700 mg Previous fragility fracture Excessive alcohol Estrogen de \201 ciency Prolonged immobilization Breast feeding women No advice 1250 mg Family history of fragility fracture Low dietary calcium For average calcium content in typical foods see: http://ods.od.nih.gov/ factsheets/calcium .asp Co-morbidities (e.g. RA) Vitamin D de \201 ciency The UK NOS and others have questioned whether, for people with osteoporosis and the elderly , these amounts are suf \201 cient. Intrinsic risk factors \200 As the skeleton ages, BMD, and skeletal integrity dimin- ishes. Age is an important determi nant of fracture risk. Probably through an effect on having larger bones and BMD, an Afro-C aribbean skeleton is protected from the age-related effects in skeletal mass and bone quali ty compared with Caucasian and Asian origin skeletons. Estrogen has important protective ef fects on the skel- eton. Rapid bone loss follows estrogen de \201 ciency in early post-men opausal women. Also, lower levels of oes- trogen measured in established post-menopausal wo men have been related to rates of bone loss. Studies are not conclusive on what family hist ory of frac- ture constitutes an increased risk. The most relevant risk factor is a materna l hip fracture at a young age, say <70 years. Lesser degrees of fracture risk are possibly associ- ated with a history of a fragility fracture in a \201 rst degree female relative and father. A number of conditions and medications are associated with an increased risk of PMO. Nutrition: vitamin D Vitamin D facilitates calcium absorption. Over 90% of the body \200\231s vitamin D is deriv ed (synthesized) in a UV-depen- dent mechanism in skin. An age-related decline in solar exp osure and metabolic ef \201 ciency underscores the reason for widespread vitamin D de \201 ciency in the elderly. \200 The best current estimate for the lower limit of normal levels of vitamin D (by measurement of 25-OHD) is 30 g/l (75 nmol/l). Oral intakes of vitamin D are generally low, although if UV-triggered skin generation of vitamin D is adequate, an oral intake of vitamin D is no t necessary. In the USA and Canada, milk is forti \201 ed with vitamin D. Margarine and ce reals are often carry small amounts of vitamin D. Generally, the best food source of vitami n D generally is oily \201 sh, e.g. mackerel, salmon or sardines. Higher serum 25-OHD has been associated with higher BMD (NHANES III), improved lower limb neuromuscular function a nd fewer falls in elderly women. Lifestyle risk factors \200 Leanness [body mass index (BMI) <20 kg/m2] is a strong risk factor for fracture. It is depe ndent on BMD. Incremental changes in BMI above 20 kg/m2 are not pro- tective. Both mechanic al effects of body mass on bone and greater circulating oestrogens after the menopause have been proposed as reasons for a protective effect of obesity. A lack of mechanical stimuli increases bone resorption. Hence, prolonged immobility causes a net loss of bone. Higher fr acture risk in women who smoke is partly, although not wholly explained by lower BMD. Proba ble contributory factors to risk include lower body weight, earlier menopause and enhanced degradation of circu- lating estrogen in smokers. Excessive alcohol has a number of effects : reducing gonadal hormone production, interfering with calcium absorption and vitamin D me tabolism, affecting protein metabolism, causing sarcopaenia and increased falls risk. Alcoh olics often also have poor nutritional intake. Hormones Estrogen de \201 ciency is a major risk for PMO. \200 Estrogen loss increases bone turnover activation fre- quency and contributes to remodeling imbalances though de-repressed effects on osteoblast generated IGF-1, osteoprotegerin, and TGFB, for example, and bone marrow cytokines, such as Il-1, Il-6, and TNFA. The hypo-oestro genic effects on fracture risk depend on its duration and severity, but also age-related BM D and skeletal integrity. Thus, the short-term fracture risk from hypo-oestrogenaemia in yo ung women taking (certain) contraceptives is different to that in 51-year-old women just go ing through the menopause. Other determinants of bone strength Factors such as bone geometry and trabecular connectiv- ity are undoubtedly important determinants of bone strength and fracture risk (see Plate 3 1). \200 It is likely that variations in skeletal geometry achieved during skeletal growth are in \202 uenced by a complex integral of genetic and environmental factors. CHAPTER 14 Bone diseases 399 Very low calcium intake is a risk factor for PMO. Such severe calcium de \201 ciency is us ually a consequence, in part, of vitamin D de \201 ciency. There is some controversy over whether mild or moderate calcium de \201 ciency is an independent risk for fracture. High salt and caffeine intake may be risks for fracture. Increased calcium excretion may explain the risk. The list of conditions, which are associated with low BMD and increased bone tur nover, is long. Many, but not all of these conditions, have been shown to increase the risk of fracture risk in women. A condition or long-term treatment associated with osteoporosis is an indication to measure BMD. Key features in the history \200 Relevant points in the history are derived from a review of clinical risk factors (see abov e). Broadly, the history should explore age of menopause, co-morbidities, and use of medica tions associated with osteoporosis, nutrition, family history of fracture, previ- ous fract ures, and falls history (and causes thereof). Table 14.4 Falls risk factors Example causes Previous falls Gait, balance, mobility, and muscle weakness Sarcopaenia Some conditions and medications which increase the risk of osteoporosis \200 Perceived functional ability and fear of falling Low con \201 dence; walking unaided Endocrine diseases: hyperparathyroidism, Type 1 diabetes, hyperthyroidism, Cushing \200\231 s, hyperprolactinaemia. Chronic in \202 ammatory diseases: rheumatoid arthritis, ankylosin g spondylitis, Crohn \200\231s disease, coeliac disease. Neuromuscular diseases: paraplegia , multiple sclerosis. Cancer: breast cancer, multiple myeloma. Transplantation. Pregnancy-i nduced osteoporosis. Anorexia nervosa. Rare conditions (e.g. osteogenesis imperfecta, masto - cytosis, homocystinuria). Medications: \200 \200 \200 \200 Visual de \201 ciency Poor eyesight; use of bifocals when walking Cognitive impairment Dementia \200 \200 \200 \200 \200 Incontinence Diuretics; bladder pathology; neurological disease. Home hazards Trip hazard; poor lighting Cardiac pathology or medications Hypotension secondary to bradycardia or medications Some speci \201 c medications and polypharmacy Salt loss from diuretics (hypotension); dizziness from benzodiazepines glucocorticoids; aromatase inhibitors; long-term low molecular weight heparin; anticonvulsa nts. Key features on examination A review of appendicular skeletal and pelvic fracture features is beyond the scope of this text. Please refer to orthopedic texts. BMD (bone mass) as a risk factor for osteoporosis \200 Vertebral fractures (VFs) \200 \200 Prospective studies show the risk of osteoporotic frac- ture increases continuously as BMD declines. There is a 1.5 \200\2233-fold increase in risk of fracture for each standard devi ation (SD) fall in BMD. A greater accuracy of fracture risk can be obtained by a site-speci \201 c BMD assessment. The highest gradient of risk is at the hip (2.6). BMD at different sites can be used to predict the future risk of fracture at the same or other sites. Curre ntly BMD assessment is integral to overall oste- oporosis/fracture risk assessment. VFs are not always associated with pain. Multiple VFs in the thoracic spine can cause kypho sis. Kyphosis is not always due to VFs (e.g. multiple level intervertebral disc disease and biomechanical causes). Christmas tree pattern folds of skin falling down on the back can i ndicate multiple VFs (although is not speci \201 c). The lower rib cage can approximate to the iliac rim when the patient is standing if multiple VFs have caused substantial height loss. Falls (see Table 14.4) \200 