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 A fall is a prerequisite for a distal forearm and hip frac- ture in the majority of people. Falls increase with age particularly in post-menopausal women. Though just 1% of falls in the elderly leads to a fracture, a fall in the year preceding a wrist or hip fracture in th e elderly is very common. There are numerous risk factors for falls, which in turn should b e considered risks for osteoporotic fracture in elderly post-menopausal women. Clinical features PMO, though conventionally diagnosed on the basis of BMD (see below) is characterized clini cally by fragility frac- ture. PMO can predate any clinical symptoms or signs. Figure 14.3 DXA scanner. POST-MENOPAUSAL OSTEOPOROSIS 400 Investigations DXA scanning \200 Table 14.6 Interpretative aspects of DXA Since 1994, a consensus report from The World Health Organization (WHO) has resulted in wid espread adop- tion of a de \201 nition of PMO based on measurement of BMD from hip, spine, or forearm expressed in BMD standard deviation units (T-scores). DXA technique using appro priate software can estimate BMD at sites in the femoral neck, lumbar spine, forearm, and t he whole skeleton. The T-score de \201 nition of osteoporosis has been adopted for men, bu t should not be used for children, adoles- cents, and premenopausal women. Greatest accurac y of speci \201 c fracture prediction derives from its site-speci \201 c BMD measurement. Hip and spine BMD are the best overall predictors of any fracture. Peripheral DXA scanners allow forearm bone BMD to be measured. Although forearm bone osteoporosis can be diagnosed , generalized PMO is not predicted well by low forearm BMD. As there are a number of techni cal issues regarding scan acquisition and interpretation there are a number of constraints on the use of DXA. DXA: technical or interpretative issue Possible consequence BMD measure may re \202 ect any condition, which affects bone mineralization in scanned ar ea BMD estimated from mineralized content of bone scanned BMD is estimated from an area (not volume) of bone May falsely elevate vertebral body BMD from a spine where there is degenerative disease at any depth under scanned area Affects scanning acquisition \200\223 accuracy and precision. Gross obesity, ascites, or skeletal soft-tissue calci \201 cation in scanned area Interpret scans cautiously if a condition is present that causes sclerotic, but fragile bon es (e.g. renal osteodystrophy) High BMD may not always denote bone strength May have low BMD in one place, but not the skeleton generally (e.g. low forearm BMD from se lective effects of hyperparathyroidism) General assumptions from single site BMD measurement Quantitative (heel) ultrasound (QUS) \200 T-Score = Measured BMD - young adult mean BMD Young adult BMD standard deviation (SD) Though no de \201 nition of PMO using quantitative ultra- sound exists and it cannot be us ed to diagnose oste- oporosis, QUS may have a role in indicating and managing osteoporotic fracture risk. QUS machines are con \201 gured to measure broadband ultrasound attenuation (BUA) or speed of sound (SOS) through the os calcis. QUS scanners are portable and cheap. Both BUA and SOS predict hip fracture in post-menopausal women partly independently of DXA- derived BMD. T-Scores were originally intended to be used only to interpret BMD results in post-menopaus al women Table 14.5 World Health Organization (WHO) de \201 nitions of osteoporosis and T-score cla ssi \201 cation of BMD in women T-score Interpretation T \211 \200\2232.5 Osteoporosis \200\223 the BMD result is equal to, or more than, 2.5SDs below the young adu lt mean BMD T \211 \200\2231, but is > \200\2232.5 Osteopaenia \200\223 the BMD result is between 1 and 2.5 SDs below the young adult mean BM D T > \200\2231 Normal \200\223 the BMD result is less than 1 SD below the young adult mean BMD See p. 401 for use of BMD in FRAX. Spinal imaging \200 Obvious vertebral fracture is shown on using DXA- based vertebral fracture analysis (VFA) o r conventional lateral spinal radiographs (see Plate 29). Detecting mild vertebral fracture , where little change in shape of the vertebral body has occurred, is dif \201 cult using radiographs or VFA. There is a recognized pattern of appearance of vertebral body osteoporo sis with MR, which can be useful to rule out malignancy-associated causes of fracture. Semi quantitative scales of vertebral morphology (e.g. after Genant or Jiang/Eastell) applied to conven- tional lateral spinal radiographs are useful for grading vertebral deformity and f racture for the purposes of studies. Knowledge of the scales and their derivation is useful for bone physicians, rheumatologists and radi- ologists. Figure 14.4 Lumbar fracture shown on lateral radiographs (left) and using DXA (Vertebral As sessment Mode). Images from differ- ent patients (from ORL Osteoporosis, with permission). CHAPTER 14 Bone diseases 401 QUS may be useful to identify people at higher risk of low BMD measured by DXA and thus be used to reas- sure people that a DXA scan is not needed. All major therapeutic osteoporosis studies, which have proved fracture prevention, have done so in people who \200\231ve had a fracture, and/or low hip and/or spine BMD measured by DXA. Fracture prevention using bisp hos- phonates or strontium ranelate has not been shown on patients de \201 ned at risk on the basis of QUS. The attributes of QUS suggest it may play a role in help- ing physicians manage osteoporosis risk. As no measure of bone mineral content or BMD is made, it cannot b e used to diagnose osteoporosis. Bone histopathology This is the gold-standard method for diagnosing osteopo- rosis. A trans iliac undecalci \201 ed bone biopsy is required. \200 In practice obtaining a bone biopsy for routine diagnosis of osteoporosis is inappropriatel y invasive, costly, and infeasible, but also, if obtained on iliac bone, might be viewed as from an inappropriate skeletal site. Biopsy is best reserved to clarify bone disease where multiple aetiologies may exist (e.g. associated with long- term anticonvulsants or in rena l bone disease). In PMO \201 ndings are: cortical and trabecular bone de \201 cit with t rabeculation of endocortical bone and poor trabecular connectivity. Dynamic indices (e.g. a ctivation frequency \200\223 the probability that a remodeling cycle will begin at any poi nt) vary considerably. Other imaging \200 Conventional CT and bone scintigraphy can be helpful in some cases in characterizing fractu re (e.g. pelvic), but are not routinely used to diagnose osteoporosis. Quantitative compute d tomography (QCT) has been used in research to determine the true three-dimen- sional volu metric BMD of trabecular-rich bone. Using digital X-ray radiogrammetry (DXR), BMD of the me tacarpals can be inferred from digitized radiographs of the hand. DXR has been shown to pre dict regional osteoporosis in certain condition, such as rheumatoid arthritis. FRAX (WHO fracture risk assessment tool) The FRAX tool evaluates fracture risk for patien ts. It is based on individual patient models integrating risks associ- ated with clinical r isk factors and femoral neck BMD. See www.shef.ac.uk/FRAX \200 FRAX is based on data from large population cohorts (men and women). FRAX provides a 10y pr obability of fracture. FRAX can be applied for individuals in different countries. In the U K, FRAX on-line links directly to an online resource detailing guidance for therapy (NOGG). \200 \200 Laboratory investigations \200 PMO typically occurs, existing without any abnormal laboratory test abnormalities. Frequent ly clinical, DXA, and other imaging investiga- tions cannot discriminate PMO from secondary causes of osteoporosis. Laboratory tests are then indicated. Frequently conditions causing secondary osteoporosis can be clinically silent or dif \201 cult to detect clinically (e. g. subclinical hyperthyroidism, primary hyperparathy- roidism, early osteomalacia, or myelo ma). A high index of clinical suspicion is needed, although it would be prudent to consider a screen of laboratory tests regard- less of clinical assessment where DXA scan has shown osteoporosis on T-score WHO criteria. References Blake GM, Wahner HW, Fogelman I. Technical principles of X-ray absorptiometry. I n: Blake GM, Wahner HW, Fogelman I, eds, The Evaluation of Osteoporosis. London: Martin Dun itz, 1999: 55. Chang K, Center J, Nguyen ND, et al. Incidence of hip and other osteoporotic fractures in e lderly men and women: Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 2004; 19: 532 \200\2236. Clunie G. The diagnosis of osteoporosis. In: Clunie G, Keen R, eds, Osteoporosis. 2007:17 \200\22332. Grados F, Marcelli C, Dargent-Molina P, et al. Prevalence of verte- bral fractures in Frenc h women older than 75 years from the EPIDOS study. Bone 2004; 34: 362 \200\2237. ISCD. The writing group for the ISCD position development con- ference. Exec. Summary. J Clin Densitom 2004; 7: 7 \200\22312. Laboratory tests useful in identifying causes of osteoporosis in post-menopausal women or c onditions contributing to increased fracture risk in PMO \200 \200 \200 \200 \200 Jiang G, Eastell R, Barrington NA, Ferrar L. Comparison of methods for the visual identi \201 cation of prevalent vertebral fracture in osteoporosis. Osteoporos Int 2004; 15(11): 8 87 \200\22396. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17: 1726 \200\22333. Serum calcium, phosphate, ALP, albumen. 25-hydroxyvitamin D, PTH. TFTs, LFTs, creatinine (a nd estimated GFR). Serum and urine protein electrophoresis. Coeliac antibodies (e.g. tTG). Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B. Ten year proba- bilities of osteoporotic fractures according to BMD and diagnos- tic thresholds. Osteoporos Int 2001; 12: 989 \200 \22395. O \200\231Neill TW, Felsenberg D, Varlow J, et al. The prevalence of verte- bral deformity in European men and women: the EVOS. J Bone Miner Res 1996; 11: 1010 \200\2237. Given that fragility, osteoporotic fracture can occur in elderly post-menopausal women at \200\230osteopaenic \200\231 levels of BMD above the T-score threshold ( \200\2232.5 < T \211 -1), it is wise to consider laboratory tests in some women who have had fragility fra ctures and osteopaenia, say at a cer- tain age such as \211 65 years old. Thompson PW, Taylor J, Dawson A. The annual incidence and sea- sonal variation of fractures of the distal radius in men and women over 25 years in Dorset, UK. Injury 2004; 35: 462 \200\2236. WHO Scientific group on the assessment of osteoporosis at primary health care level., 2004. Available at: www.who.int/chp/ topics/osteoporosis.pdf; THERAPEUTICS OF POST-MENOPAUSAL OSTEOPOROSIS 402 Therapeutics of post-menopausal osteoporosis Acute fracture management The orthopedic management of acute fracture is beyond the scope o f this text though Rheumatologists may be required to manage medical problems in such patie nts, ad- vising on pain control and investigating underlying causes of fracture. All post-m enopausal women who have had a fracture should be investigated for osteoporosis. General bone health measures There are some simple measures, which are logically and intuit ively appropriate to recommend to post-menopausal women, regardless of any BMD measurement and speci \201 c fracture risk assessment to maximize the chance of main- taining good ske letal health in the long-term: \200 \200 \200 \200 \200 Stop smoking. Reduce alcohol. Remain mobile and weight bearing. Remain vitamin D replete (> 75 nmol/l or >25 g/l). Avoid suboptimal dietary calcium intake specifically avoiding seco ndary hyperparathyroidism. Pain control Fracture units typically work to protocols for acute pain relief from fracture . \200 There is some evidence that calcitonin injection 100 \200\223200 iu subcutaneously bd has a nalgesic properties. Its effect on fracture healing is not precisely known. Intolerance owi ng to effects of vasodilation is common. There is some debate over whether IV bisphosphonat e given at the time of vertebral fracture is appropriate. Reducing bone turnover with bisph osphonate may impair fracture healing. Only anecdotal reports suggest ef \201 cacy at redu cing pain. Added to this list and for the elderly, we might reasonably add the identi \201 cation and addressing of factors, which would lead to an increased falls risk. It is important also to address the above for women who are recommended to take speci \201 c treatment (see below). When to recommend speci \201 c drug treatment Most guidelines recommend treatment on the b asis of high relative risk of fracture expressed by low hip or lumbar spine BMD, speci \201 cally a T-score of \200\2232.5 or less. This ap- proach, however, leads to some young post-menopausal women with a low T-score, but low risk of fracture being treated and some elderly women with T-scores higher than \200\2232.5 not being treated despite a high risk of fracture primarily because of their age. Vertebroplasty Vertebroplasty is the percutaneous injection of bone cement into painful fra ctured vertebrae. \200 Vertebroplasty has been shown to reduce pain from both acute and chronic fractures in >85% patients. The effect is most notable with acute fractures. Pretreatment MR is important to identify symptomatic level, de \201 ne posterior cortical margin, ensure pedicles are inta ct, characterizes the appearance of the fractured vertebra, and can point to other patholog y, which might be contributing to the pain. Polymethylmethacrylate cement is used. The main com- plication is extravasation of cement into soft-tissues and epidural space. The most s erious complication, although rare, is cement leakage into para-vertebral veins and consequ ent pul- monary emboli. Other complications include spinal cord compression and acute radic ulopathy, pain, and fever, and slight increase in risk of fracture of adjacent vertebral bo dy. Current and future practice determining which women will \200\230bene \201 t \200\231 fro m treatment is based on an integration of 4 aspects of fracture risk assessment (e.g. FRAX) . \200 Age: an important risk factor for fracture, chie \202 y inde- pendently of BMD. BMD: for e ach SD decrease in BMD, the relative risk of fracture increases by about 2.5. Previous frag ility fracture: which roughly doubles any risk estimate of future fracture. Clinical risk f actors: based currently on some evidence, but mostly assumption, that the more risk factors there are, the higher the fracture risk, again partly independent of BMD. Kyphoplasty Kyphoplasty describes the injection of cement into a bal- loon, which has been in \202 ated within a collapsed vertebra. It aims to restore vertebral anatomy and spinal deformity, and is more technically demanding than vertebroplasty. \200 40 30 Achieving restoration of vertebral height in the acute setting is a more realistic aim than where vertebral frac- tures are chronic. The procedure is safer than vertebroplasty given the containment of injected cement within the balloon. % 20 10 0 Fracture prevention Objectives of treatment The over-arching importance of managing PMO is to pre- vent fractures. Thus, PMO management includes: \200 50 55 60 65 70 75 80 85 Age Choice of, and supervising adherence to, long-term drug therapy. Avoiding lifestyle habits and general \200\230ill-health \200\231 factors that can increase fracture risk and survei llance for. Addressing, any conditions evolving over time that can contribute to bone fragi lity. T= \210\2221 T= \210\2222.5 T= \210\2222.5/# Figure 14.5 The 10-year risk of hip fracture (%) in post-meno- pausal women. Integrating ag e, BMD T-score, and previous fracture (#) into a risk assessment (graph from data derived c hie \202 y from Kanis et al., 2001, and adapted). CHAPTER 14 Bone diseases 403 Thus, as shown in Figure 14.5, even if a 55-year-old woman has a T-score of \200\2232.5 an d has had a fracture, her 10-year risk of having a hip fracture is <5%; in fact lower than a 70-year-old woman who might have a higher T-score (of \200\2231) and has not had a fract ure. The integration of risk from individual fracture risk factors (with BMD) \200\224see FRAX (www.shef.ac.uk/FRAX) \200\224has been widely adapted in guiding decisions about ther apy. Table 14.7 Choices for treating PMO Treatment for PMO Fracture prevention: a crude synthesis of strength of evidence data and size of prevention effect Vertebral Non-vertebral HRT ++ +/- Raloxifene ++ Pharmacological treatment (See Table 17.4) Ef \201 cacy of drugs in PMO is measured in ter ms of fracture prevention. The 3 main ways drugs can work to reduce fracture incidence are by increasing bone mass, reducing bone turnover, and improving (or maintaining) the struc- tural integrity of bone. Etidronate ++ + Alendronate +++ ++ Risedronate +++ ++ Ibandronate (oral) +++ + Zoledronate (IV) ++++ ++ Hormone replacement therapy (HRT) \200 Strontium ranelate +++ ++ In randomized-controlled trials (RCTs), HRT protects against loss of BMD, either as combine d estrogen- gestagen preparations or as unopposed estrogen ther- apy in hysterectomized wom en. Oral, transdermal, and percutaneous delivery all show ef \201 cacy. Con \202 icting d ata for anti-fracture ef \201 cacy of HRT can be summarized from: \200 rhPTH ++++ + Bisphosphonates: oral Bisphosphonates localize to bone mineral surfaces ex- posed by osteoc lasts then inhibit osteoclast activity. Bone turnover is reduced; trabecular bone tends to retain its connectivity and bone mass increases. \200 Wells \200\231 meta-analysis, which concludes that HRT is associated with a non-signi \201 cant reduction in risk of vertebral (RR 0.66; 95%CI 0.41 \200\2231.07) and non-verte- bral (RR 0.87; 95%CI 0.71 \200\2231.08) fracture, respectively; the Women \200\231s Health Init iative (WHI) studies, which showed unopposed estrogen in 10 739 post-meno- pausal hysterect omized women was associated with a hazard ratio for hip fracture of 0.61 (0.41 \200\2230.91 ) and in 16 608 women with an intact uterus (given estrogen + gestagen) was 0.66 (0.45 \200 \2230.98) Daily oral Alendronate, Risedronate, and Ibandronate and intermittent Etidronate (400 mg da ily for 14 days continuous once in every 13-week cycle) have all been shown to reduce the r isk of vertebral fracture. The entry criteria for index studies of the above have differed slightly (e.g. based on age, baseline BMD, frac- ture history, etc.), but basically, each t herapy is associ- ated with a 35 \200\22360% relative risk reduction in vertebral fracture rates over placebo \200\223 in (probably generally) vitamin D replete women (except Etidro nate) without substantial secondary hyperparathyroidism. Further studies have shown intermi ttent dosing (weekly for Alendronate 70 mg and Risedronate 35 mg and monthly for Ibandronat e 150 mg) results in similar changes in lumbar spine BMD occur over 1 \200\2232 years as da ily dosing of the same drug. Such \200\230bridging \200\231 studies use BMD as a surrogate marker of anti-fracture ef \201 cacy. The same degree of trial rigor is not evident for s tudies where non-vertebral fracture has been the end-point. Studies suggest anti-hip (and o ther non-vertebral) frac- ture efficacy for daily Alendronate and Risedronate essentially, but only where baseline osteoporosis risk indices were most marked (e.g. very low BMD and o r multiple fractures). Similar, but fewer data exist for Ibandronate. Larger improvements i n lumbar spine BMD with bisphos- phonates are associated with larger decreases in verte- br al fracture risk. Non-adherence with bisphosphonates long-term is sig- ni \201 cant and as sociated with reduction in fracture pre- vention effect. Management strategies that increas e patient contact and supervision while on treatment have been shown to improve compliance. Oral bisphosphonates can cause upper GI side effects, diarrhea, arthralgia, and occasional ly rashes. Oral bisphosphonates are absorbed poorly and need to be taken fasting (with wate r) then (ideally) patients need to wait 60 min before taking food, drink, or other medicati ons. In recommending HRT for osteoporosis, it s bene \201 ts (including the relief of climacter ic symptoms) needs to be balanced against the adverse effects: \200 an increased risk of breast cancer and coronary heart disease in women with an intact uteru s receiving com- bined estrogen + gestagen therapy; an increased risk of stroke and venous thrombo- embolism (VTE) in women receiving both estrogen only and estrogen + gestagen thera py. HRT thus would arguably be best considered in women with premature menopause where it might have a rela- tively low risk of side-effects (i.e. where the background rate of breast can cer, coronary and cerebral vascular dis- ease, and VTE is relatively low). Selective estrogen receptor modulators (SERMs) \200 SERMs are non-steroidal partial estrogen agonists in bone, but act as antagonists in reprod uctive tissues. Raloxifene is the only SERM currently licensed for the treatment and preven tion of PMO. Raloxifene suppresses bone turnover and prevents bone loss though effects are less potent than with estrogen, in-keeping with partial agonist activity. In the MORE trial (7705 post-menopausal women), the risk of vertebral fracture risk was signi \201 cantly r educed with raloxifene 60 mg daily (RR 0.7; 95%CI 0.5 \200\2230.8). Although Raloxifene exe rts a similar effect on risk of vertebral fracture compared with HRT, no bene \201 t was f ound in terms of risk of hip fracture. THERAPEUTICS OF POST-MENOPAUSAL OSTEOPOROSIS 404 Oral bisphosphonate anti-fracture ef \201 cacy has been determined only in studies where a ttempts have been made to keep patients replete in vitamin D and calcium. It is convention to provide daily vitamin D3 and calcium supplements with bisphosphonate therapy. SR is formulated as granules, which are dissolved in water therefore SR is drunk. Ideally, SR needs to be taken at least 2 h after food and drink, and at least 2 h before. The main s ide-effect with SR appears to be gut intoler- ance (diarrhea). Increased risk of VTE and Dr ug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been reported, wi th the former listed as a relative contraindication to use. Bisphosphonates: intravenous Owing to intolerance of oral medications, small bowel dis- ease/malabsorption, poor adheren ce, or inef \201 cacy, it may be necessary to consider intravenous therapy. Historically P amidronate has been used (e.g. 30 \200\22360 mg every 3 \200\2234 months), although no robu st study data are available show- ing anti-fracture ef \201 cacy. Currently, 2 bisphosphon ates \200\223 Ibandronate and Zoledronate \200\223 are licensed for use to treat PMO. \200 Recombinant human parathyroid hormone (rhPTH) Intermittent parathyroid hormone (PTH) has a stimulatory effect on bone turnover, which preferentially affects bone formation over resor ption (as opposed to continuous bone exposure to PTH which overall results in bone loss thr ough excessive resorption). Therapeutic PTH has been manufactured as recombinant human PTH (amino acids 1 \200\22334 or 1 \200\22384). \200 Ibandronate 3 mg (bolus injection) given once every 3 months shows changes in BMD and bone turnover markers equivalent to changes seen with oral Ibandronate doses associated with ver tebral fracture reduction. It is tolerated well. Zoledronate 5 mg given as yearly infusions reduces vertebral fractures by 70%, hip fractures by 41% and all non-vertebral fractures b y 25% over 3 years in PMO. Adherence to treatment (return for serial yearly infu- sions) wa s very high in the study. Common side effects with all IV bisphosphonates appear to be mild fever, myoarthralgia and transient acute phase response ( \202 u-like illness in 25 \200 \22340%). These side effects may be reduced by continuous calcium supplementation through t he treatment period. Acute uveitis and osteonecrosis of the jaw (ONJ) are rare, but recogni zed side effects from IV bisphospho- nates. Most ONJ cases have been in cancer patients tre ated with recurrent infusions many of whom had had cranial radiotherapy and/or poor dentiti on. Acute nephritis and renal failure have been reported with Zoledronate. Atrial \201 br illation may be a rare side effect of Zoledronate infusion. 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.