2. Abnormal chest radiograph: The chest radiograph may show nodules, cavities, or in \201 ltr ate 3. Urinary sediment: Microscopic hematuria or red cell casts 4. Histological changes of granulomatous in \202 ammation on biopsy 5. PR3-ANCA (C-ANCA) positivity Pulmonary disease \200 80% of cases have pulmonary disease. \200 The classic pulmonary manifestation is cavitary parenchymal lesions, mimicking infection or malignancy. The tracheobronchial tree may be locally involved before any signs of generalized disease. Subglottic pseudotumors and/or stenosis cause stridor or dyspnea. Lower bronchial stenosis may cause atelectasis and obstructive pneumonia. Multiple nodules with or without cavitatio n may be found in the lungs of asymptomatic patients. Severe pulmonary disease is associated with alveolar capillaritis, hemorrhage, and hemoptys is, with ground glass in \201 ltrates on computed tomography (CT). The radiograph typicall y shows an alveolar or mixed alveolar \200\223interstitial pattern; the appearance may mimi c pulmonary edema and focal infection. Renal disease \200 Up to 90% of patients with generalized ( \200\234severe \200\235) GPA have renal involvement. Renal involvement can range from milder focal and segmental glomerulonephritis (GN) to fulminant diffuse necrotizing (rapidly progressive) and crescent ic GN, which may rapidly lead to end stage renal disease. The milder form of the condition is not common, manifesting in the asymptomatic patient as a nephritic picture of microscopic hematuria, active sediment, and mild renal impairment. Skin disease \200 40% of cases have skin disease. \200 Features include palpable purpur a due to a leukocytoclastic vasculitis, necrotic papules ( \200\234Churg-Strauss nodules \200\235), livedo reticularis, and pyoderma gangrenosum. CHAPTER 15 Primary vasculitides 432 Musculoskeletal symptoms \200 Musculoskeletal symptoms are observed in 60% of cases. \200 Symptoms can range from mild myalgias (in 50% of the cases) and arthralgias to overt arthritis. 20 \200\22330% of rheumatic symptoms may be related to a no nerosive and nondeforming polyarthropathy. Migratory arthralgias are a classic presentation for WG. Nervous system \200 About one-th ird of patients with GPA have involvement of the nervous system. Mononeuritis multiplex and distal sensorimotor polyneuropathy are the main lesions. Seizures and cerebritis are much less frequent events. Disseminated granulomatous lesions ( \200\234pachymeningitis \200\235) can spread to the retropharyngeal area and skull base with involvement of cranial nerves I, II, III, V I, VII, and VIII; pachymeningitis can also be associated with diabetes insipidus and mening itis. Eye disease \200 Granulomatous lesions may obstruct the nasolacrimal duct and cause orbit al pseudotumor, with optic nerve compression from masses developing in the retrobulbar spac e. Rarely a purulent sinusitis may spread and cause secondary bacterial orbital infection. Manifestations in the generalized stage of GPA include scleritis, episcleritis (red eye), vasculitis of the optic nerve, and occlusion of retinal arteries, i n addition to the granulomatous lesions described above. Investigation of GPA \200 Laboratory investigation should include ANCA, CBC with differen tial, routine chemistries, ESR, CRP, and urinalysis to look for an active sediment. Not all patients with GPA will be ANCA-positive; a negative ANCA test does not necessarily exclude this diagnosis. When suspicion of kidney disease exists, renal biopsy may be useful to con \201 rm a diagn osis of GPA, and may provide prognostic information as well. Sinus biopsies con \201 rm a diagnosis of GPA in only 33% of cases; biopsy often shows non speci \201 c evidence of in \202 ammation, and is most useful to exclude concomitant infe ction or malignancy. Pulmonary nodules are often asymptomatic; a patient diagnosed with GPA should undergo some form of chest imaging, regardless of symptoms. Treatment and prognosis of GPA is discussed with the other AAV, below. This page intentionally left blank CHAPTER 15 Primary vasculitides 434 Other forms of AAV: microscopic polyangiitis (MPA) and eosinophilic granulomatosis with pol yangiitis (EGPA) Microscopic polyangiitis (MPA) \200 MPA is classi \201 ed as a pulmonar y-renal (hemorrhage) syndrome, a group that also includes Goodpasture \200\231s disease and systemic lupus erythematosus. GPA and cryoglobulinemic vasculitis may also present as a pu lmonary-renal syndrome. MPA lacks the granulomatous manifestations characteristic of WG, such as sinus disease, sub glottic stenosis, and pulmonary nodules. \200 Unlike GPA, MPA is characterized by MPO-ANC A antibodies, which are associated with a P-ANCA staining pattern. Up to 80% of patients wi th MPA will be ANCA-positive. Like PAN, the male:female ratio is 2:1, with the majority of patients being Caucasian. The mean age of presentation is 50 years. Most patients with MPA will present with renal involvement in the form of a necrotizing glomerulonephritis, similar to what can be seen with GPA. Unlike most forms of vasculitis, glomerulonephritis from AAV is \200\234pauci-immune \200\235 (i.e., there is only minimal immunoglobulin deposition on immuno \202 uorescence stains). Pulmonary hemorrhage presents as hemoptysis, and can be surprisingly subtle in some patients. Although classically described as a life-threatening manifestation, younger patients may be minimally symptomatic. Bronchoscopy with bronchoalve olar lavage will demonstrate hemosiderin-laden macrophages. Chronic pulmonary capillaritis may eventually lead to pulmonary \201 brosis. Other clinical features of the disease are shown in Table 15.8. Eosinophilic granulomatosis with polyangiitis (EGPA; Churg \200\223Strauss syndrome) \200 This condition is often described as a clinical triad of adult-onset asthma, eosinophilia, and vasculitis. Typically, the asthma gradually worsens in intensity until the patient requires daily oral steroids for symptom control. Many of these patients will have been treated with a leukotri ene inhibitor (although leukotriene inhibitors do not cause the disease). Peripheral blood hypereosinophilia is typically mild, and resolves quickly upon treatment with oral corticosteroids. Other manifestations of hypereosinophilia include \200\234 \202 eeting \200\235 pulmonary in \201 ltrates, myocarditis, and interstitial nephritis; frank glomerulonephrit is is much less common in this diagnosis. Nerve involvement is a common manifestation of vasculitis among patients with the CSS, and patients should be examined for evidence of a sensory neuropathy or mononeuritis multiplex. OTHER FORMS OF AAV 435 Table 15.8 Clinical features at presentation (as % of cases) in classic polyarteritis nodos a, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg \200 \223Strauss syndrome) Clinical feature Polyarteritis nodosa Microscopic polyangiitis EGPA Renal impairment 25% 90% 50% Pulmonary disease 40% 50% General 50%, asthma 100% Fever 60% 40% Skin vasculitis 40% 50% 50% Gastrointestinal disease 45% 20% 60% Cardiovascular disease 15% 20% 45% Peripheral neuropathy 10% 10% 60% Ear, nose, and throat 10% 20% Ocular disease 10% 20% Classically, it is said that the asthmatic component improves dramatically after the onset of the vasculitis, although this is often not the case. Cutaneous granulomas that form along the elbows and \201 ngers are called \200\234Churg-Strauss nodules \200\235; ironically, they appear more commonly i n association with GPA. ANCA-associated vasculitis: treatment and prognosis The AAV are approached using the same t reatment strategy, which con- sists of a remission induction phase and a remission maintena nce phase. Remission induction \200 In the United States, it is standard to use a modi \201 ed Nati onal Institutes of Health protocol for the treatment of \200\234severe \200\235 systemic v asculitis (i.e., vasculitis that threatens life or the function of a vital organ): oral cyc lophosphamide (CYC) 2mg/kg/day (1.5 mg/kg/day in the elderly or in patients with renal insu f \201 ciency) for 6 months, followed by an antimetabolite steroid sparing agent (MTX, AZA ) for 1 year or longer. Rituximab 375 mg/m 2 IV weekly for four weeks has been approved by the US Food and Drug Adm inistration for the treatment of granulomatosis with polyangiitis (Wegener \200\231s granul omatosis) and microscopic polyangiitis, and may also be effective for the vasculitic manife stations of eosinophilic granulomatosis with polyangiitis CHAPTER 15 Primary vasculitides 436 (the Churg-Strauss syndrome). Patients should be premedicated with methylprednisolone 60 \200\223125 mg IV prior to each infusion. Prednisone 1mg/kg/day (up to 80 mg/day) for the \201 rst month is used in conjunction wit h cyclophosphamide or rituximab. Patients with rapidly progressive disease may bene \201 t from initial treatment with methylprednisolone 1 g IV daily for 3 days. Pulse IV CYC (15 mg/kg IV every 2 weeks for 6 weeks, then every 3 weeks for 6 months) is as effective as oral CYC for remission induction, but is associated with a higher risk of rel apse. Patients with renal failure due to glomerulonephritis or pulmonary hemorrhage may also bene \201 t from plasmapheresis. Patients with mild disease may be treated with oral MTX 20 \200\22325 mg weekly and prednisone 0.5 mg/kg/day for remission induction. Patients receiving CYC should also receive trimethoprim/sulfamethoxazole for prophylaxis against P. jiroveci pneumonia (PCP). Patients receiving chronic steroids sh ould receive osteoporosis prophylaxis. Remission maintenance \200 Once remission has been achieved with CYC, a less toxic drug m ay be used for remission maintenance. MTX and AZA (1.5 \200\2232.0 mg/kg/day) are both stan dard remission-maintenance drugs, but mycophenolate mofetil (2 \200\2233 g/day) and le \202 unomide (20 \200\22330 mg/day) may also have a role in the treatment of some patients. Patients should receive remission maintenance therapy for at least 1 \200\2232 years, or lo nger in patients with a history of relapsing disease. \200 There are limited data support ing the use of rituximab 500 mg every 6 months for remission maintenance. This strategy may be particularly useful for patients who have previously failed other remission- maintenanc e strategies. Other treatments \200 Among patients with renal failure due to ANCA-associated vasculitis , plasmapheresis improves short-term renal survival, but does not improve long-term renal s urvival or overall mortality. IV immunoglobulin (0.4 g/kg/day for 5 days) may be used for remission induction in patients at high risk of systemic infection. Anecdotal reports have shown the bene \201 t of in \202 iximab in combination with methot rexate or cyclophosphamide for treatment of resistant vasculitis, although this is highly c ontroversial in the United States, and has fallen out of favor. Case series demonstrate som e ef \201 cacy in patients with refractory disease, but in exchange for a high risk of inf ectious complications There is evidence that respiratory tract infections may trigger a relapse of GPA. Trimethop rim-sulfamethoxazole in patients with stable disease on maintenance therapy may decrease re spiratory infection, and is also useful for prevention of PCP among patients treated with C YC. Other vasculitides \200 Most other forms of vasculitis are treated by analogy to the ANCA - associated vasculitides, with severe forms being treated with cyclophosphamide and high dos e glucocorticoids (e.g., prednisone OTHER FORMS OF AAV 437 1 mg/kg/day), and milder forms treated with methotrexate, azathioprine, or other anti-metab olites, in addition to lower dose glucocorticoids (e.g., prednisone 0.5 mg/kg/day). The major exception to this rule is giant cell arteritis, which is typically treated with glucocorticoids alone. Treatment of a vasculitis associated with an infectious disease (e.g., hepatitis B-associat ed PAN, hepatitis C-associated cryoglobulinemic vasculitis) should always include treatment of the underlying pathogen whenever possible. Prognosis Prior to the introduction of cyclophosphamide and steroids, mortality associated with generalized AAV approached 100%. Modern immunosup- pressive regimens have transformed these diseases into chronic condi- tions, characterized by cycles of relapse and remission. For many patients, the consequences of treatment (such as steroid-associated complications ) may lead to greater morbidity than the underlying disease itself. Mortality due to infect ion continues to be an important consideration for patients treated for AAV; indeed, patien ts with \200\234treatment resistant \200\235 AAV should be carefully evaluated for the pre sence of Nocardia , Aspergillus , and other infections that can mimic some of the manifesta tions of the AAV. CHAPTER 15 Primary vasculitides 438 Small-vessel and single organ vasculitis The de \201 nition of small vessel vasculitis is open to different interpretations. Small vessel disease can be one feature of granulomatosi s with polyangii- tis (Wegener \200\231s granulomatosis), microscopic polyangiitis, and eos inophilic granulomatosis with polyangiitis (the Churg \200\223Strauss syndrome). However, t here are a range of clinical and pathological features that de \201 ne a speci \201 c gro up of small-vessel vasculitides outlined in Table 15.9. Patients who have a small-vessel va sculitis restricted to the skin who do not have evidence of a systemic vasculitis (or anoth er rheumatic diseaes) are now thought of as having a \200\234single organ vasculitis \200 \235. Leukocytoclastic vasculitis \200 Histologically, leukocytoclastic vasculitis appears as a neutrophilic in \201 ltrate in and around small vessels, with fragmentation of the neutrophils (leukocytoclasis), \201 brin deposition, and endothelial cell necrosis. Immune complex deposition appears to b e important in pathogenesis. \200 Small-vessel vasculitis usually presents in the skin, a lthough the microvasculature of any tissue may be affected, especially joints or kidneys. Some forms of cutaneous vasculitis are predominantly lymphocytic, without evidence of neutr ophils or leukocytoclasis. However, the division into leukocytoclastic and non-leukocytocla stic (lymphocytic) vasculitis is not absolute. Likewise, the clinical presentation of cutan eous vasculitis can vary considerably. The \201 nding of leukocytoclasis should prompt a thorough review of drug treatment (e.g. , sulfonamides, penicillin, thiazides), a search for infection (hepatitis B, human immunode \201 ciency virus, B -hemolytic streptococcus), a screen for autoimmune rheumatic disease , malignancy (in particular myelo- and lymphoproliferative diseases), in \202 ammatory bow el disease, chronic active hepatitis, and cryoglobulinemic vasculitis (see below). Allergic (hypersensitivity) vasculitis \200 Allergic vasculitis is the most common patter n of presentation in adults, both sexes being affected equally. Nonblanching hemorrhagic papules (palpable purpura), purpuric macules, plaques, pustules, bullae, and ulcers may occur, classically distributed maximally over the lower leg. A low-grade fever, arthralgias, and microscopic hematuria may accompany such presentation. Often the condition is self-limiting and identi \201 able causes should be managed as appropriate. Analgesia may be needed and systemic steroids may be required fo r acute organ disease, especially progressive renal impairment. Dapsone (100 mg po daily), hydroxychloroquine (400 mg po daily), or colchicine (0.6 mg po t wice daily) may help decrease the frequency or severity of manifestations in some patients. AZA (2 mg/kg/day) may be appropriate for refractory disease, but removal of the offending d rug or exposure is the most effective treatment strategy. SMALL-VESSEL AND SINGLE ORGAN VASCULITIS 439 Table 15.9 Conditions associated with small-vessel vasculitis Leukocytoclastic vasculitis Allergic vasculitis (hypersensitivity angiitis): drugs, infection, in \202 ammation, autoi mmune disease, malignancy, Henoch \200\223Sch nlein purpura Urticarial vasculitis (hypocomplementemic vasculitis) Cryoglobulinemic vasculitis Hypergammaglobulinemia Erythema elevatum diutinum and granuloma faciale Non- leukocytoclastic vasculitis Drugs (penicillins, thiazides) Nodular vasculitis (see \200\230panniculitis \200\231) Livedo vasculitis (Lymphocytic vasculitis) Pityriasis lichenoides Henoch-Sch nlein purpura \200 This tends to be regarded as a special form of allergic vasculitis. It occurs most often in children but can affect young adults as well. \200 Ig A is usually detected in skin, gut, or renal biopsies. If suspected, one should request dir ect immuno \202 uorescence (DIF) in advance, since this requires special processing of the biopsy. The classic presentation is with purpura, arthritis (50%), hemorrhagic GI disease (40%), and glomerulonephritis (50%). Corticosteroids given early may relieve joint and GI symptoms but there is little evidence that they prevent progression of renal disease or in \202 uence o verall outcome. If renal function is rapidly deteriorating, pulsed methylprednisolone and/o r plasmapheresis may be of bene \201 t. Patients who present with a nephritic or nephrotic syndrome have an increased lifetime prev alence of renal complications, including hypertension. Although most cases are self-limited, this can (rarely) become a chronic, relapsing disease. Such patients should be evaluated for the presence of a monoclo nal IgA antibody, which may herald a pre- malignant lesion, and is often refractory to ther apy. Urticarial vasculitis \200 Urticarial lesions with arthralgias are the most common featur es of this condition, with men outnumbering women 2:1. The typical age of onset is 40 \200\22350 years. Morphologically, the skin lesions resemble ordinary urticaria and sometimes may be mistaken for erythema multiforme. Unlike ordinary urticaria, the lesions o f urticarial vasculitis tend to last for days (not hours) and tend to be burning and painfu l (not pruritic). Patients are generally classi \201 ed as having normocomplementemic or hypocomplementemic urticarial vasculitis, with the latter being more frequently associated with systemic compl aints. CHAPTER 15 Primary vasculitides 440 Patients with hypocomplementemic urticarial vasculitis tend to develop more systemic featur es such as renal, GI, and pulmonary disease. Less common manifestations include lymphadenop athy, uveitis, and benign intracranial hypertension. These patients are often ANA positive, and some may evolve into SLE. Systemic antihistamines are widely used but tend to be disappointing. Several antihistamine s used in combination at higher-than-normal doses may be needed to see a clinical response. There are anecdotal reports of success with indomethacin, hydroxychloroquine, colchicine, cyclosporine, and dapsone. AZA (2.0 \200\223 2.5 mg/kg/day) or sulfasalazine (1g po twice daily) may be particularly effective. For the majority of patients, the condition is chronic and benign. The normocomplementemic form of urticarial vasculitis may be self- limited in some patients. Fo r those with end-organ damage, chronic immunosuppression may be necessary. Cryoglobulinemic vasculitis \200 Cryoglobulins are immunoglobulins that precipitate when cold. They are divided into three types: type I (monoclonal), type II (mixed monoclonal and polyclonal), and type III (polyclonal). Mixed cryoglobulins are associated with autoimmune rheumatic diseases, infection, and lymph oproliferative disorders. Hepatitis B and C viral infection should always be excluded; the latter in particular is strongly associated with mixed essential cryoglobulinemia. Cryoglobulins are commonly present in patients with hepatitis C, and do not mandate immunos uppressive therapy in the asymptomatic patient. \200 Mixed essential cryoglobulinemic vas culitis presents with purpuric skin lesions showing a leukocytoclastic vasculitis on biopsy ; polyarthralgias (70%), weakness, progressive renal disease (55%), and transaminitis (70%) are common. Women are affected as twice as frequently as men. Less common problems include edema, hypertension, leg ulcers, Raynaud \200\231s phenomenon, abdominal pain, neuropathy, glomerulonephritis, and p ulmonary capillaritis (hemorrhage). The prognosis is worse with renal disease; the main causes of death among patients with cry oglobulinemic vasculitis include renal failure and infection. Treatment requires management of the underlying cause; immunosuppression by itself is frequently unsatisfactory. Choice of immunosuppression shoul d be dictated by the disease manifestations; the most severe forms may require treatment wi th cyclophosphamide, pulse steroids, and plasmapheresis. Rituximab may also be effective, p articularly for patients with hepatitis C-associated cryoglobulinemic vasculitis who cannot be treated with antiviral agents, but relapse after cessation of therapy is common. Hypergammaglobulinemic purpura \200 This is a rare, benign IgM condition presenting as lo ng-standing leukocytoclastic purpura similar to the cutaneous features of Sj gren \200\231s syndrome (see Chapter 12). SMALL-VESSEL AND SINGLE ORGAN VASCULITIS 441 It should not be confused with Waldenstr m \200\231s macroglobulinemia, a monoclonal IgM paraproteinemia associated with lymphoma. Erythema elevatum diutinum (EED) and granuloma faciale (GF) \200 These are rare but disti nctive forms of chronic localized leukocytoclastic vasculitis. There is no systemic involvement and the etiology is unknown. EED is characterized by slowly enlarging edematous purplish-brown plaques or blisters over the backs of the hands, elbows, or knees. They heal very slowly (m onths to years) with \201 brosis. It may respond to dapsone. GF presents as single or multiple pink-brown, well-de \201 ned, smooth papules and plaques on the face. They persist for years. It is distinguished histologically from EED by the presence of eosinophils and a normal collagen beneath the epidermis. It ma y respond to intralesional steroids. Nonleukocytoclastic (lymphocytic) vasculitis \200 The differential diagnosis of nodular f orms of cutaneous vasculitis embraces a wide range of disorders, including the panniculitides (see Chapter 18). Erythema induratum (nodular vasculitis) is regarded as a distinct group characterized by recurrent subcutaneous nodules usually found on the legs of young to middle-aged women. Erythema induratum is more likely to present on the posterior aspect of the legs than is erythema nodosum, which tends to appear on the anterior aspect. Patients are otherwise healthy. Streptococcal infection may be found. The term \200\234Bazin \200 \231s disease \200\235 is sometimes used to describe the nodular vasculitis that can occur in association with tuberculosis. The condition often resolves spontaneously but may take m any years. Intralesional triamcinolone or dapsone (100 mg po daily) may help. Livedoid vasculopathy is characterized histologically by endothelial proliferation and intraluminal thrombosis leading to ischemic damage. Patients typically pr esent with painful ulcerations of the lower extremities. Livedoid vasculopathy has been att ributed to elevated levels of plasminogen activator inhibitor-1. Similar lesions can be see n in the antiphospholipid syndrome, so a diagnosis should not be made based on the appearan ce of the lesions alone. The lesions heal with white atrophic scar ( \200\234atrophie blanc he \200\235). Pressure stockings, subcutaneous heparin, and assiduous wound care may all he lp with the resolution of the active lesions. Pityriasis lichenoides is a uncommon disorder of pink papules which enlarge rapidly and may become hemorrhagic before becoming necrotic and heal with scarring. It is usually self-limiting and may respond to ultraviolet B irradiation. CHAPTER 15 Primary vasculitides 442 Kawasaki disease \200 This is a febrile, acute vasculitic illness of childhood. It is pro bably more common than rheumatic fever as the cause for rheumatic heart disease in children <5 ye ars of age and is associated with coronary artery aneurysms, myocarditis and myocardial inf arction. Other organs involved include liver, pancreas, and kidney. It is seen most often in Japanese Americans with a peak prevalence age of 18 months to 2 years, and is more common in males, ratio 5:1. Fever is usually present for >5 days and associated with conjunctivitis, erythema, and edema (skin, lips, and pharyngeal), and lymphadenopathy. Join t in \202 ammation may also occur during the acute phase. Myocarditis may appear early but arterial aneurysm formation appears later, its risk of occ urring increases after longer periods of being febrile (14 \200\22316 days). There are no speci \201 c blood tests. Acute phase markers are usually high and cultures negative. An ECG and echocardiogram may show conduction defects and myocardial in \202 ammation, respectively. Treatment should start with IVIG (2 g/kg) administered over 8 \200\22312 hours and aspirin (80 \200\223100 mg/kg/day, divided into 4 doses). Patients w ho fail to respond may bene \201 t from re-treatment with IVIG, or pulse methylprednisolon e therapy. The role of plasmapheresis and anti-TNF- A therapy is less clear. For further information, the reader is referred to the 2004 Scienti \201 c Statement from the American Heart Association on the diagnosis and management of Kawasaki \200\231s disease. 1 1 Newburger JW et al . Diagnosis, Treatment, and Long Term Management of Kawaski Disease. C irculation, 2004; 110: 2747 \200\22371. 443 Chapter 16 Metabolic bone diseases and disorders of collagen Osteoporosis 444 Osteomalacia and rickets 454 Parathyroid disease and related disorders 458 Paget \200\231s disease of bone 466 Miscellaneous diseases of bone 470 Molecular abnormali ties of collagen and \201 brillin 474 CHAPTER 16 Metabolic bone diseases 444 Osteoporosis \200 Osteoporosis can be de \201 ned as a decrease in bone mass and strengt h resulting in an increased risk of fracture. Unlike osteomalacia, the ratio of matrix to m ineral deposit in bone is normal in osteoporosis. The World Health Organization de \201 nes osteoporosis on the basis of bone density compar ed to the mean bone density for a young adult; this is known as a T-score. Osteopenia refer s to bone mineral density (BMD) that falls 1.0 \200\2232.5 standard deviations (SD) below t he BMD of a young adult. Osteoporosis is used if the BMD falls more than 2.5 SD below the B MD of a young adult. The risk of osteoporotic fracture is greater in women than in men; in both sexes, risk of fracture varies with site (see Table 16.1). \200 The age-adjusted inc idence of hip fractures has been increasing steadily. The Centers for Disease Control and Prevention note that 345,000 hip fractures oc cur annually in the United States, and the incidence increases with age. The annual inciden ce of a hip fracture in a 65-year-old woman in the United States is 1.6 per 1,000. Recent e stimates places the cost of in-patient and community care at $8 billion. Pathogenesis and classi \201 cation (see Table 16.2) \200 During childhood and adolescen ce, growth and modeling lead to an increase in the size, shape, strength, and composition of bone. Growth ceases with the clos ure of the growth plates (epiphyseal cartilage). However, remodeling and mineral homeostasi s continue throughout life with bone resorption and deposition coupled by the interaction b etween osteoclasts and osteoblasts, respectively. Peak bone mass, or maximal bone density, is usually achieved in the third decade. Peak bone mass is determined by both genetic (e.g. vitamin D receptor gene polymorphism, estrogen re ceptor \200\223cytokine interaction), and environmental factors. Changing lifestyle and beh avior patterns have been suggested as a effective ways of increasing peak bone mass. Table 16.1 Risk of osteoporotic fracture with site Fracture site Overall lifetime risk of fracture (%) Men Women Hip 6.0 17.5 Vertebral 5.0 15.6 Distal forearm 2.5 16.0 Any of above 13.1 39.7 OSTEOPOROSIS 445 Table 16.2 Classi \201 cation of osteoporosis Major type Causative factor(s) Details Primary (physiological) Postmenopausal Age-related Idiopathic Juvenile onset Endocrine Hyper parathyroidism Secondary Hypopituitarism Thyrotoxicosis Hypogonadism Cushing \200\231s syndrome Insulin- dependentdiabetes Drugs Corticosteroids Excess thyroxinereplacement Heparin Anticonvulsants Cyclosporine A Hemopoietic Multiple myeloma Lymphoma Leukemia Mastocytosis Gaucher \200\231s disease In \202 ammatory diseases Rheumatoid arthritis Ankylosing spondylitis Congenital Osteogenesis imperfecta Immobilization Idiopathic hypercalciuria Osteoporosis of pregnancy CHAPTER 16 Metabolic bone diseases 446 After the age of 35 (presumably due to declining osteoblast activity), the amount of bone l aid down is less than that resorbed during each remodeling cycle sequence. The net effect i s an age-related decrease in bone mass. Trabecular and cortical bone mass decline by approx imately 6% and 3% per decade, in women and men, respectively. Further bone loss occurs at the time of menopause with declining ovarian function and levels of estrogens. Up to 15% of bone mass can be lost over the 5-yea r period immediately after menopause. A further 15% of bone mass can be lost if vitamin D d e \201 ciency coexists. \200 The mechanism of age-related bone loss is unknown. Several possibilities exist: \200 Decreased intestinal calcium absorption \200 Decreased synthe sis of vitamin D \200 Hyperparathyroidism (caused by the above) \200 Increased osteobla st function \200 Fatty in \201 ltration of the bone marrow, leading to loss of precursor cells and locally generated growth factors. Bone mineral density measurement is speci \201 c but not sensitive for identifying patient s at high risk of fracture. Almost 50% of postmenopausal women over 50 years old who have a n osteoporotic fracture do not have osteoporosis based on their T-score. Conversely, treati ng all patients based on T-score generally overtreats younger women, who may be at low risk of bone fracture despite their T-score. To address this shortcoming, the World Health Organization has developed a Fracture Assessment Tool (FRAX) to identify patients at highest risk for osteop orotic fractures. The clinical risk factors identi \201 ed by FRAX include: \200 Age \200 Sex \200 Prior fragility fracture \200 History of corticosteroid use ( (cid:2) 5 mg qd for (cid:2) 3 months) \200 Parental history of hip fracture \200 Rheumatoid arthr itis \200 Secondary osteoporosis (e.g., type 1 diabetes, hypogonadism, premature menopaus e, chronic malabsorption, longstanding hyperthyroidism) \200 Current smoker \200 Alcoho l use of greater than 2 drinks daily \200 Low body mass index. The complete FRAX tool is available online at www.shef.ac.uk/FRAX \200 Bone mineral densi ty measurement should be considered in any patient with these risk factors, or in any woman older than 65. Because of lack of data, it is dif \201 cult to know if older men also ben e \201 t from routine screening in the absence of known risk factors for osteoporotic frac ture (such as concurrent glucocorticoid use). Idiopathic osteoporosis \200 Idiopathic osteoporosis de \201 nes occurrence of the condi tion in pre-menopausal women or men under the age of 60 years, with no OSTEOPOROSIS 447 apparent cause. The female: male ratio is 10:1. Most cases are found to have \200\234low b one turnover \200\235 with low rates of bone formation. Some cases have \200\234high bone turnover \200\235 with hypercalciuria; these cases may respond to antiresorption drugs such as calcitonin and bisphosphonates. It is not clear if the majority of patients in this group will bene \201 t from therapy. For most patients with idiopathic osteoporosis, in the absence of other risk factors, the absolute risk of fracture remains low. Anticatabolic (antiresorptive) agents a re unlikely to shift the risk of fracture signi \201 cantly. Juvenile idiopathic osteoporosis ( JIO ) \200 Juvenile osteoporosis (JIO) is an uncommon disorder that occurs before or at onset of puberty. It affects the sexes equally. The cause is unknown and there are no consistent biochemical abnormalities (see Table 16.3). The child presents with pain, nontraumatic fractures around the weight-bearing joints, and collapsed vertebrae. No speci \201 c treatment is available and for most, bone mass increases to normal values as puberty progresses; however, in some cas es fractures may lead to deformity. Supportive physical therapy should be made available. \200 In the same way that height and weight charts are used to assess childhood development, there may be a role for serial bone density measurement in children with known low bone mass, as a surrogate assessment of appropriate development. Table 16.3 The causes of juvenile idiopathic osteoporosis Type Causative factor(s) Primary Calcium de \201 ciency Idiopathic Osteogenesis imperfecta Secondary Endocrine (see Table 16.2) Intestinal: malabsorption biliary atresia type I glycogen storage disease Inborn errors of metabolism \200\224homocystinuria Leukemia Congenital cyanotic heart disease CHAPTER 16 Metabolic bone diseases 448 Glucocorticoid-induced osteoporosis ( GIO ) \200 GIO is a major concern. Treatment should be offered to all patients taking prednisone for a period likely to be >3 months. The risk is present at doses as low as 2.5 mg daily, although data would suggest it increases consi derably for doses > 5mg daily. There is con \202 icting evidence about the effect of inhaled corticosteroid on fracture r isk. Patients on maximal doses of inhaled corticosteroids should be assessed for additional risk factors for osteoporosis and may require prophylaxis. The pathogenesis of GIO is controversial. Corticosteroids can affect calcium and phosphate metabolism both directly and indirectly in bone, kidney, and the intestine. Possible mechan isms are shown in Table 16.4. Primary hyperparathyroidism Primary hyperparathyroidism is a relatively common disorder wit h an adult prevalence of about 0.2% in the \201 fth to seventh decades of life. It is thr ee times more common in women than men, due to an increased incidence after the menopause. Mild hyperparathyroidism is often diagnosed after an incidental \201 nding of hypercalcem ia on routine blood tests. The manage- ment of this condition will be discussed later in th is chapter. Table 16.4 Possible pathogenesis of corticosteroid-induced osteoporosis Mechanism Site Effect Reduced bone formation Osteoblasts Reduced activity Reduced recruitment Reduced collagen synthesis Reduced growth hormone Reduced cytokine levels Adrenal \200\223testis Reduced gonadal hormones Increased bone resorption Adrenal \200\223testis Reduced gonadal hormones Parathyroid Increased PTH Intestinal Reduced calcium absorption Reduced sensitivity to vitamin D Renal Reduced calcium resorption Muscle Decreased muscle mass OSTEOPOROSIS 449 Hypogonadism \200 Hypogonadism due to any cause may lead to an increased risk of osteoporotic fracture. Causes of amenorrhea include primary ovarian failure, use of estrogen antagonists (e.g., in the management of endometriosis), hyperprolactinemia, anorex ia nervosa, and low body mass index (e.g., elite sportswomen). Causes of decreased testosterone levels include Klinefelter \200\231s syndrome, hypogonadotrophic hypogonadism, hyperprolactinemia, anorexia nervosa, and testicu lar dysfunction following mumps orchitis. Hyperthyroidism Hyperthyroidism leads to osteoporosis as a consequence of high bone turnove r, enhanced osteoclast recruitment, and increased bone resorption. Malignancy Malignant in \201 ltration and replacement of marrow tissue occurs in multiple myeloma, lymphoma, leukemia, systemic mastocytosis, and diffuse bone metastases. Mechanisms differ, for example: \200 Overproduction of osteoclast-activating cytokines (such as IL- 1 and TNF) in myeloma. Local synthesis of 1,25-hydroxyvitamin D by malignant cells in lymphoma. Overproduction of heparin, histamine, and prostaglandins that stimulate osteoclasts in mastocytosis. Other factors Potential factors that may cause generalized osteoporosis in in \202 ammator y disorders, such as RA and AS, include the systemic effects of in \202 amma- tory product s, alterations in sex hormones, altered calcium metabolism, changes in load bearing, and th e effect of drugs used in treatment. Immobilization per se leads to a net loss of bone (rat es as high as 5% per month in the \201 rst 6 months). Evaluation of osteoporosis and low-trauma fracture \200 Low-trauma fracture in those aged 50 \200\22375 years should be investigated to exclude the possibility of osteoporosis. The three most common sites of fracture are the wrist, vertebrae, and hip. Many now consider a low-trauma fracture in a person >75 years of age as strongly suggestive of osteoporosis an d would treat without measuring bone mass. Assessment and investigation for possible underl ying disease is still required. Plain radiographs are an insensitive method of assessing bone mass. The high correlation between bone mineral density (BMD) and bone strength and, therefore, b one fragility has led to the development of several techniques for assessing BMD. The standard technique for measuring BMD is dual energy X-ray absorptiometry (DEXA). It is quick, has high resolution, precision and accuracy, and can as sess the lumbar spine, femoral neck, wrist, and whole body. DEXA gives two readings, the \200\234T \200\235 and \200\234Z \200\235 scores. CHAPTER 16 Metabolic bone diseases 450 The T score is the individual \200\231s bone mineral density compared with the mean bone de nsity achieved at peak bone mass for the same sex (and, more recently, race). The Z score i s the individual \200\231s bone mineral density compared with the mean bone density for som eone of the same age and sex (and, more recently, race). Most analyzes and studies have foc used on the T score. The score is recorded as a + or \200\223 \201 gure above or below t he mean. For every one standard deviation (SD) below the mean there is a twofold increase i n the risk of fracture, i.e., an individual three SD below the mean has an eightfold risk o f fracture compared with a \200\234normal \200\235 individual of the same age, bearing in mind also that base-line risk increases with age in the \200\234normal \200\235 population . Quantitative CT allows volume measurements and can distinguish between cortical and trabecu lar bone in vertebrae. It is, however, costly and entails a high radiation exposure. Ultrasonography is a noninvasive technique that is currently being correlated with DEXA. US can be performed at the heel (calcaneus) and patella. Correlation seems poor and its role in clinical diagnostics remains unclear. Since the advent of noninvasive techniques, transiliac bone biopsy is no longer essential u nless there is the need to diagnose osteomalacia as the underlying cause. Bone biopsy may b e used as a tool in research, in particular for the quanti \201 cation of rates of bone tu rnover.