Accretion of BMD occurs over 30 months or more with daily PTH injections. Changes also incl ude cortical thick- ening and increased trabecular connectivity. Teriparatide (rhPTH 1-34) is licensed to treat PMO. It is given as a 20 g SC injection daily for 18 months. It is s upplied in a pre- \201 lled syringe, which lasts for 28 days and must be stored at 2 \200 \2238 C. A RCT of 1600 women showed a 65% relative risk reduc- tion of vertebral fractures with rhPTH 1 \200\22334 over pla- cebo (RR 0.35; CI 0.22 \200\2230.55). The study was not powered to detect a change in hip fractures though a signi \201 cant reduction in non-vert ebral fractures overall was observed (RR 0.47; CI 0.25 \200\2230.88). Follow-up of patients after 18 months showed an anti- fracture effect of rhPTH 1 \200\22334 extending for 18 mon ths for vertebral and 30 months for non-vertebral sites. Preotact \204 /Preos (rhPTH 1 \200\22384) is licensed to treat patients at high risk of fracture at a dose of 100 g dai ly by SC injection for a maximum 24 months. Preotact \204 /Preos rhPTH (1 \200\22384) is supplied in car- tridges, which are placed in an injection pen device every 2 weeks and can be stored at room temperature for up to 1 week out of 2. A RCT in 2532 post-menopausal wom en, mean age 64 years 19% of whom only had had a previous vertebral fracture, showed that r hPTH 1 \200\22384 was associated with a signi \201 cant 58% reduction in vertebral fractur e risk. There were no data on non-vertebral fractures. Regarding patient selection: in many countries PTH treatment is targeted at patients at high risk of oste- oporosis and/or wher e other treatments have failed. Mild hypercalcaemia and hypercalciuria are common, but clin ically relatively insigni \201 cant effects. An effect of rhPTH on reducing spinal pain is also noted though it is not clear whether this is due to reduction of vertebral frac- ture s or a independent mechanism. Because of the (theoretical) risk of osteosarcoma it is advis able that patients already at risk of this tumor are not treated with PTH (Paget \200\231s disease of bone, osteoma- lacia, bone metastases and patients who \200\231ve had previous s keletal radiotherapy). Strontium ranelate (SR) Strontium is incorporated into bone where it has a long half-life. Its mechanisms of action are unclear, but may be multifactorial. \200 SR inhibits osteoclast recruitment, and activity at resorp- tion sites and potentiates oste oblast proliferation and differentiation. As a result, endosteal bone forms and trabecular volume increases (shown in rats and from transiliac bone biopsies in some patients). Stront ium appears to directly trigger calcium-sensing receptors on bone cells. Two major placebo- controlled RCTs have shown ef \201 - cacy and tolerability of SR 2 g daily in PMO. A RCT o f 1649 women with at least one vertebral frac- ture and low lumbar spine BMD showed after 3 years there was a relative risk reduction of 41% in vertebral fractures with SR compared w ith placebo (95%CI 0.48 \200\223 0.73; p < 0.001). A RCT of 5000 women showed a relative ri sk reduction in non-vertebral (including hip) fractures of 16% with SR compared with placeb o (95%CI 0.71 \200\2231.00, p = 0.05) after 3 years. Additional daily calcium and vitamin D 3 supplements are advisable with SR therapy. CHAPTER 14 Bone diseases 405 Denosumab Denosumab is a human monoclonal antibody (IgG2) that targets the receptor activat or of nuclear factor kappa B ligand (RANKL), a key mediator of the resorptive phase of bone remodeling. RANKL, produced by osteoblasts, is prevent- ing from binding its ligand RANK. Thus, Denosumab mim- ics the action of endogenous osteoprotegerin \200\223 the decoy recep tor for RANKL. Initial studies in postmenopausal women with low BMD suggest twice yearly tr eatments by SC injection increases BMD and decreases biochemical markers of bone resorption signi \201 cantly, and equivalent to changes seen with Alendronate. Fracture end-point st udies are currently in progress. Other Internet sites For average calcium content in typical foods, see http:// ods.od.nih.g ov/factsheets/calcium.asp International Bone Mineral Society. Available at: www.ibm- sonlin e.org. An organization for bone physicians facilitat- ing generation and dissemination of k nowledge about bone and mineral metabolism. Interpreting DXA and BMD measurements. See list ings at: www.noah-health.org/en/bjm/osteoporosis/ diagnosis/testing.html. ICD-10 codes M80.0 \200\2239 Osteoporosis with pathological fracture M81.0 \200\2239 Osteop orosis without pathological fracture M82* Current controversies \200 Osteoporosis in diseases classi \201 ed elsewhere (e.g. myeloma M82.0*) The nature of fracture risk assessment to guide treat- ment intervention thresholds is curr ently the focus of research (e.g. FRAX). Using such fracture risk algorithms incorporating BMD data, age, fracture prevalence, and risk factors, rather than relying on relative risk from BMD alone, has many theoretical advantages (see Tucker et al., 2007). What are the lon g-term effects of bisphosphonates? How long should treatment be continued? What is the opti mum (if any) method of monitoring treatment? BMD alone? BMD and bone markers or markers alo ne? The cost-effectivity of new (expensive) treatments is an important unresolved issue. Wh at level of fracture risk justi \201 es introduction of each preventive treatment? This qu estion raises country (healthcare system)-speci \201 c issues about when to intervene with a preventive ther- apy. It is somewhat a socio-political question too, partic- ularly if t here is healthcare rationing within a fixed budget (see Str m et al., 2007). In the UK it remains to be seen whether NICE will incor- porate absolute risk algorithms into their reco mmenda- tions for osteoporosis management. At present, not! References Adami S. Bisphosphonate anti-fracture ef \201 cacy. Bone 2007; 41: S8 \200\2231 5. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathy- roid hormone and Alend ronate alone or in combination in post- menopausal osteoporosis. N Engl J Med 2003; 349: 12 07 \200\22315. Black DM, Delmas PD, Eastell R, et al. Once yearly zoledronic acid for treatment of postmen opausal osteoporosis. N Engl J Med 2007; 356(18): 1809 \200\22322. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral frac- ture risk in postmenop ausal women with osteoporosis treated with raloxifene. J Am Med Ass 1999; 282: 637 \200\223 45. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1 \200\22384) on vertebral fracture and bone mineral density in postmenopausal women with osteopo- rosis: a randomized trial. Ann Intern Med 2007; 146(5): 326 \200\22339. Kanis JA, Adams J, Bergstrom F, et al. The cost-effectiveness of Alendronate in the management of ost eoporosis. Bone 2008; 42: 4 \200\22315. Layton KF, Thielen KR, Koch CA, et al. Vertebroplasty, \201 rst 1000 cases of a single ce nter: Evaluation of the outcomes and compli- cations. Am J Neuroradiol 2007; 28: 683 \200\2239. Ledlie J, Renfro M. Balloon kyphoplasty: one year outcomes in height restoration, chronic p ain and activity outcomes. J Neurosurgery 2006; 98: 36 \200\22342. Resources Assessment tools For algorithm to determine individuals \200\231 absolute risk of fracture with and without incorporating measurements of BMD see link at www.shef.ac.uk/FRA X/ Meunier PJ, Roux C, Seeman E, et al. The effects of strontium rane- late on risk of vertebr al fracture in women with postmenopausal osteoporosis. N Engl J Med 2004; 350: 459 \200\223 68. Tucker G, Metcalfe A, Pearce C, et al. The importance of calculating absolute rather than r elative fracture risk. Bone 2007; 41: 937 \200\22341. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and bene \201 ts of estrogen plus progestin in healthy postmenopausal women: principal results from the Women \200\231s Health Initiative randomized controlled trial. J Am Med Ass 2002; 288: 321 \200\22333. Guidelines NICE technology appraisals on the use of medicines for primary and secondary ost eoporosis. Available at: www. nice.org.uk Guidelines for professionals. Available at www.no f.org/. This is for US professionals with guidelines based on The US healthcare system. Ost eoporosis: clinical guidelines for prevention and treat- ment. RCP, London ISBN 97818601613 91. Available at: www.rcplondon.ac.uk/pubs European guidance for the diagnosis and manageme nt of osteoporosis in post-menopausal women (Kanis et al. 2008). Patient support groups Nat ional Osteoporosis Foundation (USA). Available at: www.nof.org National Osteoporosis Societ y (UK). Available at: www. nos.org.uk Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: an update on mechanisms of action an d how these relate to clinical ef \201 cacy. Ann NY Acad Sci 2007; 1117: 209 \200\22357. Str m O, Bergstr m F, Sen SS, et al. Cost-effectiveness of Alendronate in the treatment o f postmenopausal women in 9 European countries \200\223 an economic evaluation based on th e frac- ture intervention trial. Osteoporos Int 2007; 18: 1047 \200\22361. Wells G, Tugwell P, Shea B, et al. Meta-analysis of the ef \201 cacy of hormone replacemen t therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev 2002; 23: 529 \200\22339. OSTEOPOROSIS IN MEN 406 Osteoporosis in men Osteoporosis in men is under diagnosed and therefore under treated. For example in >1000 me n diagnosed with osteoporotic fractures, <10% had received medication for osteoporosis and only 1% had had bone mineral density (BMD) measurement (Feldstein et al., 2005). Osteoporosis is often caused by underlying secondary causes of bone loss such as hypogonadi sm, oral gluco- corticoids (GCs), and long-term excessive alcohol intake. These are found i n over 50% of men presenting with symptomatic vertebral fractures. Epidemiology The incidence of fractures in men is about half that in women for the same age . The known excess mortality risk a major fracture confers is greater in men compared with women. \200 Table 14.8 Causes of secondary osteoporosis in men Major causes Alcoholism; glucocorticoids (GCs); hypogonadism; transplantation Metabolic and endocrine disease Hyperparathyroidism; thyrotoxicosis; idiopathic hypercalciuria; Cushing \200\231s disease Men who have distal forearm fractures: have lower BMD than controls; have a 40% likelihood of having oste- oporosis; have a 3 and 11 times the risk of having hip and vertebral fractu res, respectively. About 50% of men with low trauma vertebral fractures have been shown to have BMD evidence of osteoporosis at the lumbar spine or femoral neck. There is great disab ility after hip fracture in men, with only 21% living independently in the community a year later, 26% require home care, and 53% needing institu- tional care. GI disease Chronic liver disease; IBD; coeliac disease; gastric surgery Iatrogenic Chemotherapy; androgen deprivation therapy (through rendering men completely hypogonadal); phenobarbitone, and phenytoin; warfarin; LMWt heparin Other Malignancy (e.g. myeloma); renal bone disease Clinical features Key features in history \200 Etiology and pathogenesis of fracture Genetic BMD varies inversely with the incidence of ve rtebral and hip fractures in men. There is likely to be a strong genetic determinant of pea k BMD contributing to primary osteo- porosis in men. \200 Previous fracture with minimal trauma particularly in proximal humerus, spine, pelvis, fore arm, or hip. A history of features of one or more of the secondary causes of osteoporosis ( e.g. alcohol consumption, GC and other drug use, low libido or erectile dysfunction, chroni c bowel symptoms, enteric intolerance to gluten containing foods). Family history of fragil ity fracture in \201 rst-degree relative particularly parent. Genetic factors account for up to 80% of the variance in peak BMD \200\223 a variation in collagen type IA1, the vitamin D receptor, vitamin D binding protein, the estrogen receptor , and insulin-like growth factor 1 (IGF-1) genes may all account for some variance in peak BMD. The genetic contribution to age-related bone loss caused by declining testosterone aro matization is unknown. Genetic, secondary pathological, and environmental fac- tors may all be relevant (see below). Key features on examination \200 Genuine loss of height, TSp kyphosis, approximation of lower ribs to iliac rim \200\223 al l can be signs of osteoporosis though are not speci \201 c. Cutaneous and other stigmata o f chronic liver disease. Signs of hypogonadism: passive demeanor, low/sparse body hair, cen tripetal obesity, small testicular size. Signs of Cushing \200\231s: centripetal obesity, s kin striae \200 Environment Men have larger bones thus a 12% greater peak BMD than women. Non-genetic deter minants of peak BMD include calcium intake, exercise, delayed puberty, and intra-uterine de velopment. \200 Co-morbidities Secondary causes of osteoporosis are common in men compared with women. Age-related bone loss after the age of 40 years contrib- utes to osteoporosis in men. It is chie \202 y non-genetic in its etiology, but data is sparse. It can be in \202 uenced by in \202 uenced by declining sex steroid concentrations, low body mass index, smoking, phy sical inactivity, impaired vitamin D production, and metabolism and secondary hyperparathyr oidism (SHPT). Age-related decrease in circulating free testosterone, adrenal androgens, gr owth hormone and IGF-1 occur in men. Each hormone has been linked to decreased bone formati on. Up to 20% of men with symptomatic verte- bral fractures and 50% of men with hip fractur es are hypogonadal. Testosterone actions on the skeleton are at least in part mediated by i ts aromatization to oestra- diol and the effect of the latter on the skeleton. BMD and frac ture risk in men associate with serum oestradiol levels more closely than with testosterone . Diagnosis and investigations The diagnosis of osteoporosis in an elderly man with fragility fracture(s) can be straightforward though in men <80 years. It is appropriate to substanti ate the diagnosis with a BMD scan. All men with fracture (or \200\230fragility \200\231 or low trauma fracture) after the age of 50 or 60 years, for example, might reasonably be ref erred for a dual X-ray absorptiometry (DXA) scan. Key issues are: \200 \200 \200 Diagnosing spinal fractures. The interpretation of DXA results. The investigations to rule out secondary osteoporosis. Diagnosing spinal fractures There is well recognized under-reporting of spinal frac- tures in men and women. CHAPTER 14 Bone diseases 407 Owing to vertebral end-plate irregularities, non-oste- oporotic vertebral deformities are c ommonly seen on radiographs of ageing men in the TSp. The deformities are often slightly we dge-shaped. BMD by DXA is often not low in men with wedge deformities of the TSp. The key a ppearance in a wedge shaped vertebra, which distinguishes the bone as fractured may be spec i \201 c cen- tral end-plate depression (scalloped appearance), rather than a linear decli ne in height (posterior to anterior). Studies are being done to quantify vertebral size and continuous changes in vertebral height in association with indices of osteoporosis (e.g. l ow BMD). Table 14.9 Investigation of causes of bone fragility in men Initial investigations Conditions Full blood count; tissue transglutaminase (tTg) antibodies; ESR; CRP Malignancy; coeliac disease 9 a.m. Testosterone and LH ( SHBG) Prolactin, FSH, thyroid function tests Hypogonadism Pituitary disease and hyperthyroidism 1e/2e PHPT; hypovitaminosis-D or osteomalacia Parathyroid hormone; bone biochemistry and 25-OHD Interpretation of DXA results \200 Liver function tests Liver disease; alcoholism In both sexes, the same inverse relationship between absolute BMD and incidence of fracture s might indicate that the same absolute BMD threshold could be used for the diagnosis of os teoporosis in men and women. Then a T-score of \200\2232.5 in women would be equivalent to a T- score of \200\2232.8. The prevalence of osteoporosis using a T-score de \201 ni- ti on of \200\2232.8 would be too low, but a T-score de \201 nition of \200\2232.5 after th e age of 50 years approximates to lifetime risk of fracture for men. There is a broad inter national agreement to use a DXA- derived hip or spine BMD T-score de \201 nition of \200 \2232.5 as the diagnostic threshold for osteoporosis in men. Urea, electrolytes, creatinine and GFR Renal bone disease 24-h urinary calcium Idiopathic hypercalciuria 24-h urinary cortisol Cushing \200\231s disease Serum and urine protein electrophoresis; PSA Myeloma; prostate carcinoma Teriparatide Teriparatide is a recombinant human PTH molecule (1-34), which reduces vertebr al fractures in men with osteoporo- sis (Orwoll et al., 2003). It is given by SC injection daily over an 18-month period. Investigations to rule out secondary causes The occurrence of a fragility fracture in a man >50 years or \201 nding of a BMD T-score of hip or spine is \200\2232.5 might rea- sona bly be taken as an indication to screen for secondary causes of bone fragility whether or n ot history or examina- tion (see above) is suggestive. Other treatments \200 Strontium ranelate 2 g daily shows anti-fracture ef \201 cacy in women, but there are no d ata for men. It would be likely to work and offers an alternative if Alendronate fails and teriparatide is unavailable. Testosterone replacement may reduce fractures and increase BMD in hypogonadal men. Its role in eugonadal men is not yet known. Treatment All men with osteoporosis should be counseled about the need to optimize weight [ BMI < 19 is associated with gen- eralized osteoporosis, but obesity (BMI > 30) associated w ith hypovitaminosis-D and SHPT], stop any smoking, re- duce alcohol if excessive and consid er regular weight-bear- ing exercise. \200 Resources See under Post-menopausal osteoporosis References Feldstein AC, Nichols G, Orwoll E, et al. The near absence of oste- oporosis tre atment in older men with fractures. Osteoporos Int 2005; 16: 953 \200\22362. Secondary causes of osteoporosis need to be identi \201 ed and addressed. Calcium and vita min D supplements should be advised to maintain repletion in vitamin D (e.g. 25-hydroxyvita - min D >75 nmol/l) and to avoid SHPT. The most robust evidence for drug therapy comes from studies of Alendronate and teriparatide (rhPTH). The use of the on-line fracture risk tool (www.shef.ac. uk/FRAX) can apply for men, as well as for women. In the UK an online link t o a site providing guidelines for treatment (NOGG). Orwoll ES, Ettinger M, Weiss S, et al. Alendronate treatment of osteoporosis in men. N Engl J Med 2000; 343: 604 \200\22310. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide therapy on bone density in men with osteoporosis. J Bone Miner Res 2003; 18: 9 \200\22317. Ringe JD, Faber H, Farahmand P, Dorst A. Ef \201 cacy of Risedronate in men with primary a nd secondary osteoporosis: results of a 1 year study. Rheumatol Int 2006; 26: 427 \200\2233 . Bisphosphonates Oral (daily) Alendronate reduces vertebral fractures in eugonadal and hypog onadal men and is licensed to treat osteoporosis in men. It would be unlikely that weekly A len- dronate would not be ef \201 cacious Weekly Risedronate is a licensed option to Alendronate for which fracture prevention data exists. GLUCOCORTICOID INDUCED OSTEOPOROSIS (GIO) 408 Glucocorticoid induced osteoporosis (GIO) Epidemiology \200 Glucocorticoids (GCs) are the commonest cause of sec- ondary osteoporosis. About 1:200 of t he population may be taking GCs in a course lasting 3 months or more. About 30% of individu als taking GCs for more than 3 years will have evidence of osteoporotic fractures. The relative risk of fracture for those taking GCs is about 2.6 for vertebral and 1.6 for h ip fractures. Fracture risk relates to GC dose and duration, low BMD, increasing age and th e underlying condition. Glucocorticoids Synthesis and secretion of sex steroids ? Calcium reabsorption from kidney ? Calcium absorption from gut ? ? PTH and PTH-sensitivity Activity ? Bone resorption ? Apoptosis ? Activity ? Proliferation ? osteoblasts osteoclasts Osteoporosis Figure 14.6 The likely major mechanisms of glucocorticoid-induced osteoporosis (GIO). Fractures can occur at a higher bone mineral density (BMD) compared with non-GC-treated pop ulations. GCs have been identi \201 ed as the commonest cause of osteoporotic fracture in the young. The prevalence of vertebral fractures in patients taking GCs is about 25 \200 \22330%. The incidence of vertebral fractures is about 13 \200\22322% (data from control ar ms of randomized trials of therapy for GIO). GIO can occur even at low doses in some patien ts (<5 mg/day). reabsorption in the kidney ultimately resulting in SHPT. A consensus for a direct molecular effect of GCs on vita- min-D metabolism is lacking, as data from animal and human studies are con \202 icting. GCs may reduce gonadal hormone production, which in turn may increase bone resorption. There is type II muscle \201 bre atrophy and decrease in Type I \201 bres in GC-treated patients. Clinical features Key features in history \200 Etiology and pathophysiology A thorough assessment of GIO requires an assessment of all osteoporosis risk factors (see \200\230Post-menopausal osteoporosis \200\231). Reviewing the diagnosis of the condition be ing treated with GC (e.g. is it really PMR?), when GCs are being taken (i.e. in the morning to reduce the risk of long- term GC dependence) and considering whether GC- sparing immuno suppressants can be introduced (e.g. can azathioprine be started \200\223 perhaps not if p atient on allopurinol or TPMT activity status low) may provide information which may help t o minimize the adverse effects of GCs. GCs cause osteoporosis through direct effects on bone formation and resorption, by affectin g bone mineral me- tabolism, and gonadal hormones. Fracture risk is enhanced through an inc reased falls tendency through GC-induced reduced muscle strength. \200 GCs reduce osteoblast proliferation and function through an effect on IGF-1, IGF-2, and TGF B1. GCs cause osteocytes apoptosis. This mechanism may be important in causing osteonecrosi s. GCs may cause negative calcium balance by a combina- tion of reducing calcium absorption by the gut and CHAPTER 14 Bone diseases 409 Key features on examination A TSp kyphosis may denote underlying spinal fractures owing to GCs, but features are not speci \201 c. Table 14.10 Assessment and managing GIO: overview Assessment Action Exclude secondarye causes of osteoporosis; obtain fracture baseline (include lateral TSp + LSp radiographs). Prior to starting GCs Investigations DXA \200 \200 The earliest signs of GIO are seen in the lumbar spine. Some studies suggest that vertebral fractures caused by GCs occur at a higher BMD than fractures seen in other types of osteop orosis. Bone loss secondary to GCs, documented by BMD, is greatest in the \201 rst 12 \200\22318 months. Over time BMD loss can be 5 \200\22310% per year. For patients not treat ed with anti-osteoporosis therapy, while on GCs, yearly BMD assessments are appropriate. When starting GCs Treat osteoporosis according to risk of fracture (e.g. use guidelines) While on GCs Minimize GC dose; ensure adherence with GCs, calcium and vitamin D and speci \201 c anti-f racture therapy; monitor BMD; consider introducing GC-sparing immunosuppressants; consider treatment failure if incident fractures occur or BMD drops signi \201 cantly on therapy Laboratory investigations Tests to rule out conditions associated with osteoporosis are pru dent when assessing patients for GIO. Undisclosed pathology relevant to bone \200\230ill-h ealth \200\231, such as myeloma, hyperthyroidism, alcoholism, and chronic kidney disease (C KD) 3 \200\2235 and hyperparathyroidism are, when considered together, not infrequently enc ountered, particularly in the elderly. See Post-menopausal osteoporosis. Reliable vertebral and non-vertebral fracture prevention data in all relevant diseases at r isk of osteoporosis, where GCs are used, have not been obtained. In The UK (2007 \200\22320 08) the only drugs licensed to treat/ prevent GIO are alendronic acid (Alendronate) and fos amax, although randomized controlled trial data sug- gests that Risedronate (Actonel) and c yclical Etidronate are all effective at preventing and treating GIO. Ibandronate, given as an intravenous bolus, prevents GC- induced bone loss and appears to prevent fractures thoug h studies were not powered to assess fracture pre- vention. Clodronate also reduces bone lo ss associated with GCs and may prevent fractures. The effects of intravenous bisphosphonate s (Pamidronate, Ibandronate and Zoledronate) on reducing fractures and bone loss in GIO are untested in large robust RCTs. Anecdotal evidence suggests bone turnover and BMD loss thou gh can be reduced signi \201 cantly. Differential diagnosis Given the frequency of conditions, post-menopausal and other seconda ry causes of osteoporosis can contribute to low BMD, and fracture risk in patients taking G Cs. Low BMD can also be due to osteomalacia/SHPT. Treatment Objectives of treatment Some patients may be treated with GCs long-term. There ar e general principles for reducing GIO risk. Sadly, numer- ous studies show that despite gui delines from various or- ganizations pertinent to different diseases and patient groups, th e extent and appropriateness of management of osteoporosis risk in patients is disappointin g. Gonadal hormone replacement \200 HRT reduces GC-induced bone loss in post-menopausal women. Fracture prevention has not been shown. Testosterone replacement should be considered in hypogonadal men on long-term GCs. Patient prefer- ences often dictate the use of testosterone. When coun- selled about its be ne \201 ts and risks, including prostate cancer, some men may choose not to be treated. If GIO risk is high, testosterone alone may not be suf \201 - cient to prevent GIO in hypogo nadal men. Calcium and vitamin D \200 Dietary increases in calcium or calcium supplements alone are insuf \201 cient to prevent GC-induced bone loss. Combination calcium and vitamin D therapy is univer- sally advised fo r patient taking GCs. It is inconclusive whether combination treatment with vitamin D is mo re effective at reducing bone loss from GCs using 25-OHD, or either calcitriol or 1A-calcid ol. Most GIO guidelines don \200\231t specify whether or how to assess calcium and vitamin- D status, although state it is important. Speci \201 c testing of vitamin-D and PTH at the outset of a long course of GCs might be prudent. If patients are replete in vitamin-D and have no SHPT, or abnormalities are slight, then advise daily calcium 0.5 \200\2231 g and vi tamin-D3 400 \200\223800 iu, while GCs are being taken. Other drugs No RCT has yet shown a fracture prevention effect of strontium Ranelate or rhPT H in GIO; however, it would be a surprise if both do not given their effects on bone bio- m arkers and BMD in GIO patients. When to introduce therapy A number of guidelines exist (see below). All highlight the need to replenish calcium and vitamin D de \201 ciency, use vitamin D and calcium combination s upplements, and introduce speci \201 c anti-fracture therapy at a higher BMD threshold tha n would happen normally. \200 Bisphosphonates \200 Numerous studies have examined the effects of a variety of bisphosphonates in reducing GC-i nduced bone loss with positive results. The case for early (primary) prevention is greatest in post-menopausal women and people wit h low BMD. As bone loss occurs within the \201 rst year, fracture risk should be assessed and decisions made about therapy for GIO when GCs are started, not at a later date. GLUCOCORTICOID INDUCED OSTEOPOROSIS (GIO) 410 Resources Guidelines American College of Rheumatology. Recommendations for the prevention a nd treatment of GC-induced osteopo- rosis, update 2001 (ACR 2001; www.rheumatology.org/ res earch/guidelines). Chronic GC therapy-induced osteoporosis in patients with obstructive lun g disease (Goldstein et al., 1999, Available at: www.chestjournal.org/cgi/content/full/116/ 6/1733). GC-induced osteoporosis. RCP (UK) 2002. Available at: www.rcplondon.ac.uk/pubs/bo oks/glucocorticoid British Society of Gastroenterology. Guidelines for osteo- porosis in co eliac disease and in \202 ammatory bowel disease, 2000. Available at: www.bsg.org.uk/. References ACR ad hoc Committee on Glucocorticoid-induced Osteoporosis. Arthritis Rheum 2001; 44: 1496 \200\223503. Goldstein MF, Fallon JJ, Harning R. Chronic glucocorticoid therapy- induced osteoporosis in patients with obstructive lung disease. Chest 1999; 116: 1733 \200\22349. Patscan D, Loddenkemper K, Buttgereit F. Molecular mechanisms of glucocorticoid-induced ost eoporosis. Bone 2001; 29(6): 498 \200\223505. Reid I. Glucocorticoid osteoporosis \200\223 mechanisms and manage- ment. Eur J Endocrinol 1997; 137(3): 209 \200\22317. Saag KG, Emkey R, Schnitzer TJ, et al. Alendronate for the preven- tion and treatment of gl ucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study G roup. N Engl J Med 1998; 339(5): 292 \200\2239. Van Staa TP. The pathogenesis, epidemiology and management of glucocorticoid-induced osteop orosis. Calcif Tissue Int 2006; 79: 129 \200\22337. ICD-10 codes M81.4 Y42.0 Drug-induced osteoporosis Glucocorticoids and synthetic analogs This page intentionally left blank OSTEOPOROSIS IN CHILDREN 412 Osteoporosis in children There is no universally accepted or robust de \201 nition of osteoporosis in children. An emerging consensus exists that for a diagnosis of osteoporosis to be made there should be r ecurrent low trauma fractures together with low bone mass or vertebral fractures. Osteoporo sis can- not be de \201 ned on the basis of low bone mineral density (BMD) alone. There ar e 3 main clinical situations: \200 and nutritional status are all likely to contribute to low bone mass in anorexia nervosa (A N). Like the adult skeleton, the growing skeleton is sensitive to the effects of various ho rmonal abnormalities includ- ing thyroxine and endogenous GC production. Secondary osteoporosis in children: the main causes Endocrine disorders/treatment \200 \200 \200 Recurrent fractures: low bone mass, but no obvious underlying condition. Secondary osteopor osis: secondary to systemic con- ditions or their treatment Primary osteoporosis: IJO \200 \223 a self-limiting pre-puber- tal condition with generalized osteoporosis \200\223 or os te- oporosis associated with an hereditary disease of connective tissue. Cushing syndrome. Growth hormone de \201 ciency. Thyrotoxicosis. Gastrointestinal disorders \200 \200 \200 \200 \200 Malabsorption (e.g. coeliac disease). Crohn \200\231s disease. Biliary atresia. Chronic hep atitis. Glycogen storage disease type 1. The other differential diagnosis of osteoporosis in children is osteogenesis imperfecta (OI ); see p. 428. Epidemiology \200 Fractures are common in healthy children: 25-40% of girls and 40 \200\22350% of boys sustai n at least one fracture during growth (peak 11 \200\22315 years). 25% fracture repeatedly. There is some epidemiological data to suggest childhood osteoporosis is more prevalent in r egions where calcium intake is low and in children with low BMD. An increased risk of osteo porotic fracture is recognized for a number of systemic conditions. Some conditions confer a potent fracture risk. The odds ratio (OR) for hip fracture associated with anorexia ner- vosa (AN) is >7. According to reviews of the topic, IJO is very rare, at least in the form originally described by Dent. IJO occurs in both sexes with a mean age of onset of 7 years (range 1 \200\22313 years) 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