See Box 71.1 for various causes of hypomagnesemia. Treatment with potassium supplementation is often unsuccessful unless magnesium is replaced at the same time. Box 71.1 Causes of hypomagnesemia GI losses \200 Vomiting \200 Diarrhea \200 Losses from \201 stulae \200 Malabsorp tion \200 Severe acute pancreatitis \200 Defective intestinal transportation caused by mutations in the TRPM6 gene Renal losses \200 Chronic parenteral therapy \200 Osmotic diuresis 71-Draznin-Chap71.indd 403 3/31/2011 3:56:42 PM CHAPTER 71 Hypomagnesemia 404 Box 71.1 (Contd.) Drugs \200 Alcohol \200 Loop diuretics \200 Aminoglycosides \200 Cisplatin \200 C yclosporin \200 Amphotericin Other causes \200 Diabetes \200 Metabolic acidosis \200 Hypercalcemia \200 Phosphat e depletion \200 Hungry bone syndrome Treatment Symptomatic magnesium de \201 ciency, especially if associated with hypoc- alcem ia or hypokalemia, requires parenteral treatment. The total de \201 cit may be of the orde r of 200 \200\223400 mEq. This should be replaced gradually parenterally. A dose of 2 g Mg SO4-.7H2O (16.2 mEq Mg) as a 50% solution every 8 hours intramuscularly ca n be given. However, as these doses are fre- quently painful, a continuous IV infusion of 4 8 mEq over 24 hours may be preferred. This should be continued until the clinical and bioch emical manifestations (hypocalcemia and hypokalemia) are resolved. In the presence of renal impairment, plasma magnesium can rise quickly, so particular care must be used if magnesium infusion is contemplated in this situation. After repletion has been achieved intravenously, or in less severe cases, treatment can be continued orally. Patients who have chronic Mg loss can be given oral supplementation of 300 \200\223600 mg o f elemental Mg in divided doses to avoid the purgative effects. In all of these instances t he dose is frequently limited by the purga- tive properties of magnesium salts. There is some evidence to suggest that the addition of calcitriol or alfa- calcidol might improve magnesium absorption. Further reading Rude R (2008). Chapter 70. Primer on the Metabolic Bone Diseases and Disord ers of Mineral Metabolism , 7th ed. American Society for Bone and Mineral Research, pp. 325 \200\223328. 71-Draznin-Chap71.indd 404 3/31/2011 3:56:42 PM INTRODUCTION 405 Osteoporosis Introduction Although the term osteoporosis refers to the reduction in the amount of bony t issue within the skeleton, this is generally associated with a loss of structural integrity of the internal architecture of the bone. The combina- tion of both of these changes means that osteoporotic bone is at high risk of fracture, after even trivial injury. Although most fractures are related to bone mass to some extent, the most common osteoporot ic fractures are those of the hip and wrist (Colles) and compression fractures of vertebral bodies. Patients who frac- ture ribs, the upper humerus, leg, and pelvis also have a highe r incidence of osteoporosis. 72-Draznin-Chap72.indd 405 4/1/2011 5:42:39 PM CHAPTER 72 Osteoporosis 406 Pathology Osteoporosis may arise from a failure of the body to lay down suf \201 cient bon e during growth and maturation; an earlier-than-usual onset of bone loss following maturity ; or an i rate of that loss. In females, the loss of estrogen at the menopause is the major etiological factor. Peak bone mass This is mainly genetically determined: \200 Racial effects (bone mass high er in Afro-Caribbean, lower in Caucasians) Family in \202 uence on the risk of osteoporosis \200\224may account for 60 \200\22370% of variation It is also in \202 uenced by environmental factors: \200 Exercise \200\224particularly w eight-bearing \200 Nutrition \200\224especially calcium Exposure to estrogen is also impo rtant. Early menopause or late puberty (in males or females) is associated with i risk of o steoporosis. Early onset of loss \200 Early menopause \200 Conditions leading to bone loss, e.g., gl ucocorticoid therapy Increased net loss \200 Aging Vitamin D insuf \201 ciency \200 Declining bone formation \200 Declining renal functio n Underlying disease states ( b see Box 72.1 ) Lifestyle factors affecting bone mass Increase \200 Weight-bearing exercise Decrease \200 Smoking \200 Excessive alcohol \200 Nulliparity \200 Poor calcium nutrition 72-Draznin-Chap72.indd 406 4/1/2011 5:42:39 PM PATHOLOGY 407 Box 72.1 Underlying causes of osteoporosis Gonadal failure \200 Premature menopause (age <45) \200 Hypogonadism in men, e.g., acqu ired and Klinefelter \200\231s syndrome \200 Turner syndrome \200 Estrogen receptor def ect Conditions leading to amenorrhea with low estrogen (for >6 months) \200 Hyperprolactinemi a \200 Anorexia nervosa \200 Athletic amenorrhea Endocrine disorders \200 Cushing \200\231s syndrome \200 GH de \201 ciency \200 Hype rparathyroidism \200 Acromegaly with hypogonadism \200 Hyperthyroidism within 3 years \200 Diabetes mellitus GI disorders \200 Malabsorption \200 Postgastrectomy \200 Celiac disease \200 Crohn \200\231s disease Liver disease \200 Cholestasis \200 Cirrhosis Neoplastic disorders \200 Multiple myeloma \200 Systemic mastocytosis In \202 ammatory conditions \200 Rheumatoid arthritis \200 Cystic \201 brosis Nutritional disorders \200 Parenteral nutrition \200 Lactose intolerance \200 Immobil ization Drugs \200 Systemic corticosteroids (when administered for >3 months) \200 Heparin (whe n given long term, particularly in pregnancy) \200 Chemotherapy (primarily by gonadal dam age) \200 Gonadotrophin-releasing hormone agonists \200 Cyclosporin \200 Anticonvulsa nts (long term) \200 Aromatase inhibition for breast cancer 72-Draznin-Chap72.indd 407 4/1/2011 5:42:39 PM CHAPTER 72 Osteoporosis 408 Box 72.1 (Contd.) \200 Androgen deprivation therapy \200 Proton pump inhibitors \200 Thiaglitizone Other causes \200 Immobilization and chronic bed rest \200 Stroke \200 Cronic cardiac disease \200 Chronic lung disease Metabolic abnormalities \200 Homocystinuria Hereditary disorders \200 Osteogenesis impe rfecta \200 Marfan syndrome Epidemiology The risk of osteoporotic fracture increases with age. Fracture rates in men ar e approximately one-half those seen in women of the same age. A woman aged 50 has approxima tely a 1/2 chance of sustaining an oste- oporotic fracture during the rest of her life. The corresponding \201 gure for men is 1/5, although this is increasing. In the United States, 10 million Americans older than 50 years of age have osteoporosis. Th ere are 1.5 million fractures each year, and another 34 million are at risk for the disease . There are approximately 500,000 hip fractures per year. These are a particular health chall enge as they invariably result in hospital admission. One- \201 fth of hip fracture victim s will die within 6 months of the injury and only 50% will return to their previous level o f independence. It has been estimated that the overall cost of osteoporotic fractures in the United States is $22 billion annually. 72-Draznin-Chap72.indd 408 4/1/2011 5:42:39 PM PRESENTATION 409 Presentation Osteoporosis is usually clinically silent until the onset of fracture. Two- th irds of vertebral fractures do not come to clinical attention. Typical vertebral fracture has the following features: Sudden episode of well-localized pain \200 May or may not have been related to injury or exertion \200 May be radiation of the pain in a girdle distribution \200 Pain may initi ally require bed rest but gradually subsides over the following 4 \200\2238 weeks. Even after this time there may be residual pain at the fractur e site. Osteoporotic vertebral fractures only rarely lead to neurological impairment. Any evidence of spinal cord compression should prompt a search for malignancy or other unde rlying cause. Following vertebral fracture, a patient may be left with persistent back pain, kyphosis, or height loss. Although height loss and kyphosis are often thought to be indicative of osteoporosis, they are more frequently the result of degenerative disease. They cannot be the result of osteop orosis in the absence of vertebral fracture. Peripheral fractures are also more common in osteoporosis. If a bone breaks from a fall fro m less than standing height, this repre- sents a low-trauma fracture that might indicate un derlying osteoporosis. Osteoporosis does not cause generalized skeletal pain. 72-Draznin-Chap72.indd 409 4/1/2011 5:42:39 PM CHAPTER 72 Osteoporosis 410 Investigation Establish the diagnosis Plain radiographs are useful for determining the pres ence of fracture. Apart from this, they are of little utility in the diagnosis of osteoporo sis. Bone densitometry In order to identify the presence of osteoporosis, it is important to act u- ally measure the bone mineral density (BMD). This is usually carried out at the hip and/ or lumbar spine with dual-energy X-ray absorptiometry (DXA). The presence of degenerative disease or arterial calci \201 cation can ele- vate the appar ent bone density of the spine without adding to skeletal strength. Increased reliance is th us being placed on measurements derived from the hip. The schema for diagnosis of osteoporosis that was proposed by the WHO has been accepted for general use ( b see Table 72.1). Biochemical markers Biochemical markers of bone turnover may be helpful in the calculation of fracture risk and in judging the response to antiresorptive therapy, but they have no role in the diagnosis of osteoporo sis. Exclude underlying causes An underlying cause for osteoporosis is present in approximately 1/3 of women and over 1/2 of men with osteoporosis. Many of the underlying causes ( b see B ox 72.1 , pp. 407 \200\223408) should be apparent from a careful history and physical exami nation. A few basic investigations are useful to exclude the more common underlying causes. Other i nvestigations may be needed to exclude other speci \201 c conditions (see Box 72.2 ). It is most helpful to target these investigations at those people who have a lower-than-expected bone mass for their age (Z score < \200\2232). Monitoring therapy Repeat bone densitometry is advocated by most, depending on cost and availability. A time i nterval of 18 months to 2 years is recommended between scans. However, in certain condition s, e.g., glucocorticoid and Table 72.1 WHO proposals for diagnosis of postmenopausal osteoporosis T score Fragility fracture Diagnosis \200\2231 Normal < \200\223 1 but (cid:2) \200\223 2.5 Low bone mass (osteopenia) < \200\223 2.5 No Osteoporosis < \200\223 2.5 Yes Established (severe) osteoporosis 72-Draznin-Chap72.indd 410 4/1/2011 5:42:39 PM INVESTIGATION 411 Box 72.2 Investigations to exclude an underlying cause of osteoporosis Useful in most patients \200 FBC \200 ESR \200 Biochemical pro \201 le \200 Renal function \200 Liver function \200 Calcium \200 Thyroid function \200 Testosterone a nd LH (only in men) \200 Vitamin D level Useful in speci \201 c instances \200 Estradiol and FSH (in women whose menopausal statu s is not clear) \200 Serum and urine electrophoresis (if raised ESR or plasma globulin is elevated) Anti-endomysial antibodies (if any suggestion of celiac disease) \200 Other investigation s for speci \201 c diseases \200 Bone turnover markers to assess drug ef \201 cacy or c ompliance and response to treatment Low-trauma fractures associated with osteoporosis Any fracture other than those affecting t he \201 ngers, toes, or face that is caused by less trauma than a fall from standing heig ht is potentially the result of osteoporosis. Patients suffering this kind of fracture shou ld be considered for investigation and/or treatment for osteoporosis. post-transplantation bone disease, more frequent measurements may be advocated. Effective treatment leads to increases of 5 \200\2238% at the spine. Bone densi- tometry ma y be replaced by biochemical markers as assays improve (e.g., P1NP). Medical management of osteoporosis Fracture risk assessment and treatment guidelines are es sential to manage- ment of osteoporosis. One of the tools is FRAX which was developed by th e WHO, in collaboration with a number of centers worldwide, l to evaluate an individual \200\231s risk of fracture during the ensuing 10 years. The population-based data incorporate clinical risk factors such as age, low BMI, smoking, oral glucocorticoid use, previous fractures, parental history of fractures, alcohol intake, rheumatoid arthritis, secondary causes of osteoporosis, and femoral neck BMD. On the basis of these risk factors, which are weighted, a score is calculated that determines an indivi dual \200\231s 10-year probability of fracture. FRAX can be viewed online. The National Osteoporosis Foundation (NOF), with consideration of FRAX, has recently revised its guidelines (see Fig. 72.1 ). 72-Draznin-Chap72.indd 411 4/1/2011 5:42:40 PM CHAPTER 72 Osteoporosis 412 2008 NOF Guidelines: postmenopausal women & men age 50 years and older 2003 NOF Guidelines: postmenopausal women Prior history of hip or vertebral fracture Prior history of hip or vertebral fracture or or T-score < \210\22220 T-score \211 \210\2222.5 or or T-score between \210\2221.0 and \210\2222.5 and 10 year probability of hip or major os teoporotic fracture \211 3 or 20% respectivelyb T-score < \210\2221.5 and one or more risk factors for osteoporosisa a We considered major risk factors (history of adult fracture, history of fragility fractur e in first degree relative, weight < 127 lbs, current smoking, or oral corticosteroid use f or > 3 months) in our application of the 2003 Guidelines. We did not consider additional ri sk factors (impaired vision, early estrogen deficiency, dementia, frailty, revent falls, lo w calcium intake, low physical activity, excess alcohol use) in our application of the 2003 Guidelines. b Calculated by the FRAX tool. Fig. 72.1 NOF guidelines for treatment of osteoporosis: comparison made between old and rev ised versions. Reprinted with permission from the National Osteoporosis Foundation. It is recommended that treatment be considered in postmenopausal women or men older than 50 years if they have low bone mass (T score between \200\2231.0 and \200\2232.5) and a 10- year probability of hip fracture (cid:2)3% or a 10-year probability of major osteoporotic-r elated fracture (cid:2)20%, based on FRAX calculations. These thresholds were determined wi th heavy empha- sis on cost-effectiveness. These guidelines are not intended to replace clinician judgment and patient preference. 72-Draznin-Chap72.indd 412 4/1/2011 5:42:40 PM TREATMENT 413 Treatment Treatments should, whenever possible, be judged by their effect on frac- ture red uction. Although some treatments are speci \201 c to certain clinical situations, there ar e also general measures that apply to all patients with osteoporosis. In addition to treatments aimed at improving bone mass, it must be remembered that fracture s can be prevented in other ways. Thus it is prudent to try and minimize the risk of fallin g by adjusting the home envi- ronment and reviewing the need for medications such as hypnot ics and antihypertensives, antidepressants, proton pump inhibitors, etc. There is con \202 icting evidence on the use of wearing hip-protecting pads. These can onl y be recommended in an institutional setting where compli- ance can be assured. Lifestyle measures \200 Smoking cessation \200 Moderate alcohol consumption. (2 glasses per day) \200 Encourage weight-bearing exercise: Impact exercise such as skipping or jumping increases bone mass. \200 Lower-impact exerci se, e.g., walking outdoors for 20 minutes 3 \227 \227 week may reduce fracture risk. Encourage a well-balanced diet. \200 Ensure adequate calcium and vitamin D intake: 1000 \200\2231200 mg elemental calcium and at least 800 IU vitamin D daily. Choice of therapy N-containing bisphosphonates Either oral or IV agents are the \201 rst line of treatment, as they are relatively cheap and are effective in reducing fractures rates by approximatel y 50% at the spine and hip. They also have a very long history of patient exposure to the d rug in clinical practice. Patients who cannot take these drugs orally may bene \201 t from IV preparations. HRT The use of estrogen or combined estrogen progesterone preparations has fallen off as a result of the \201 ndings of the Women \200\231s Health Initiative stud- ies (WHI). The d ata showed an increased risk of breast cancer and stroke that outweighed the bene \201 ts of reduction in hip fracture. The results are still considered controversial and it is recommended that estrogen be given for the shortest possible time and in the smallest effective dose to control postmenopausa l symptoms, e.g., hot \202 ashes, and other therapies, e.g., bisphosphonates, be given as \201 rst line for osteoporo- sis management. Other agents Raloxifene is recommended in females who have mainly spinal osteoporo- sis and who are at risk or have a history of breast cancer. It is not effective in reducing nonver tebral fractures, including hip. 72-Draznin-Chap72.indd 413 4/1/2011 5:42:40 PM CHAPTER 72 Osteoporosis 414 Table 72.2 Drug treatments available Spine BMD Hip BMD Treatment Effective dose # # HRT d Oral 2 mg E20 or .625 mg conjugated estrogens ++ ? ++ d Transdermal 50 mcg daily SERMs d Raloxifene 60 mg daily + + Bisphosphonates d d Alendronic acid 10 mg daily/70 mg weekly with or without vitamin D combined ++ ++ d d Risedronate 5 mg daily/70 mg weekly/ 150 mg monthly ++ + d Ibandronic acid 150 mg orally monthly or 3 mg IV every 3 months ++ + \200\223 d d Zoledronic acid 5 mg by slow IV infusion once a year for 3 years ++ ++ \200\223/d d Calcium and vitamin D 1 g + 20 mcg (800 IU) + + Calcitonin SC or IM + ? d d d ? ? Nasal 200 IU daily + ? ? Calcitriol 0.25 mcg 2x day + ? ? Parathyroid hormone 1-34 20 mcg/daily for median of 19 months +++ + \200\223 SC injections No RCT evidence However, it may be useful in patients in whom bisphosphonates are contraindicated or who are intolerant of the medication. Calcitonin given as a nasal spray is not a very effective anti-osteoporotic therapy but may reduce spinal fractures in selected patients. Strontium ranelate , although used elsewhere, is not approved in the United States. Calcitr iol is also not approved for therapy of osteoporosis in the United States. Denosumab (Prolia) is a RANK ligand inhibitor indicated for the treat- ment of postmenopaus al women with osteoporosis at high risk of frac- ture. In a 3-year randomized, double-blind , placebo-controlled trial in 7808 women aged 60 \200\22391 years, denosumab decreased new vertebral fractures by a relative risk reduction of 68%, hip fractures by 40%, and nonverte bral fractures by 20%. All fracture reductions were signi \201 cant. 72-Draznin-Chap72.indd 414 4/1/2011 5:42:40 PM TREATMENT 415 It must be administered by a health care professional. The dosage is 60 mg every 6 months a s an SC injection in the upper arm, upper thigh, and abdomen. Patients should also take 100 0 mg calcium and at least 400 IU vitamin D daily. Physicians should check serum calcium, as it must not be administered in the presence of hy poclacemia. Adverse events include skin infections and osteonecrosis of the jaw. As with ot her antiosteoporotic drugs, it should not be given to pregnant or lactating women. Teriparatide is reserved for use in postmenopausal females with severe osteoporosis at high risk of fracture (previous fractures, multiple risk fac- tors, failure or intolerance of p revious therapy). Glucocorticoid-induced osteoporosis Glucocorticoid treatment is one of the major secondary causes of oste- oporosis (Boxes 72.3, 72.4). Not all patients receiving steroid treatment l ose bone, and it is not clear what determines this. There is some suggestion that patients on corticosteroids may have bones that are more frag ile than would be suggested by the BMD. It is often suggested that such patients be treated at a higher bone density than would be case for other causes of osteoporosis (Box 72.5). Box 72.3 Most common form of secondary osteoporosis \200 Use in general population betwee n 0.5 and 1.7 % in postmenopausal women >55 years Incidence 50% in all patients treated >6 months \200 Estimated fracture incidence at sp ine and ribs in patients on long- \200 Risk of hip fracture doubled in glucocorticoid use rs term use is 15 \200\22340% Box 72.4 Etiological factors for glucocorticoid-induced osteoporosis \200 Doses of 5 mg o r greater for >3 months \200 Underlying disease itself, e.g., rheumatoid arthritis \200 Inhibition of sex steroids \200 Inhibition of calcium absorption, loss in the urine \200 Secondary hyperparathyroidism ??? \200 Direct effect on bone cells leading to incre ased apoptosis of osteoblasts and osteocytes 72-Draznin-Chap72.indd 415 4/1/2011 5:42:41 PM CHAPTER 72 Osteoporosis 416 Box 72.5 Management of glucocorticoid osteoporosis \200 DXA in patients receiving or will receive glucocorticoids for 3 months or more Intervene at T scores of \200\2231 (American College of Rheumatology) or \200\2231.5 (Royal College of Physicians) Decrease dose of glucocorticoids as rapidly as possible \200 Replace sex hormones if hypo gonadal \200 Calcium and vitamin D \200 Bisphosphonates \200 Human PTH with or withou t HRT 72-Draznin-Chap72.indd 416 4/1/2011 5:42:41 PM COMPLICATIONS OF THERAPY 417 Complications of therapy HRT Because of adverse effects (breast cancer, venous thromboembol ism, coronary disease, and stroke), HRT is no longer recommended as primary treatment for o steoporosis in normal postmenopausal women. When a woman is receiving HRT for climacteric symptoms it will pro- vide protection to her skeleton for the duration of treatment. Skeletal protection is rapidly lost on cessation of HRT. In women with a premature menopause, HRT remains the most appro- priate means of preventing bone loss in the absence of other contraindica- tions (e.g., breast cancer) (see Box 72.6 ). Women who are unable to take conventional HRT might be able to take progestogens alone (e.g ., norethisterone 5 mg daily); several of these agents have been shown to have bone-sparing properties. Box 72.6 Special considerations in premenopausal women \200 Osteoporosis in premenopausal women is rare but well recognized. The Z score should be used. It is important to exclude underlying causes of bone loss. \200 Osteoporosis can very rar ely occur in conjunction with pregnancy or lactation. This is frequently self-limiting and usually requires little treatment other than calcium supplementation. In the absence of a pre-existing fracture and continued menses, fracture risk is low. Frequ ently, all that is needed is calcium and vitamin D supplementation and lifestyle advice unt il the menopause, when more active therapy is needed to counteract menopausal bone loss. In other situations, particularly when fractures are present, most of the therapies that are used in postmenopausal women, with the exception of HRT, can be u sed (although not approved). Some caution needs to be exercised with the use of bisphosphonates in younger people: \200 Teratogenic in animals \200 Long skeletal retention time, makin g their long-term use cautious An alternative strategy is to give no treatment unless there is an osteoporotic fracture if the BMD is stable over 2 \200\2234 years. Bisphosphonates \200 Dif \201 cult dosing schedules to avoid complexing with calcium in GI tract \200 GI disturbance, including nausea, gastritis, esophagitis, and diarrhea \200 i Bone pain \200 Osteonecrosis of jaw \200 Atrial \201 brillation but no cause and effect found \200 Flu-like symptoms following IV administration \200 Possible assoc iation with atypical subtrochanteric fractures 72-Draznin-Chap72.indd 417 4/1/2011 5:42:41 PM CHAPTER 72 Osteoporosis 418 Calcium and vitamin D \200 Constipation \200 Hypercalciuria \200 Very rarely hypercal cemia Calcitonin \200 Parenteral administration \200 Flushing \200 Nausea and diarrhea Side effects are less marked following nasal administration. When given in doses of 50 \200\223 100 units IM or 200 units nasally daily, it has analgesic proper- ties and can be used in t he management of acute fracture pain. Calcitriol This has a risk of hypercalcemia and requires regular (ideally every 6 months) p lasma calcium measurements. Raloxifene \200 Similar increase in risk of venous thrombosis as HRT \200 May induce or worsen climacteric symptoms \200 Reduces risk of breast cancer Strontium ranelate (not approved in the U.S.) \200 Diarrhea \200 Venous thromboembolism \200 Strontium is incorporated into bone making bone densitometry dif \201 cult to interpret. It may affect measurement of calcium in plasma. Teriparatide \200 Contraindcations include hypercalcemia, renal impairment unexplained el evation of alkaline phosphatase, Paget \200\231s disease, prior irradiation. Risk of hypercalcemia is not great and no speci \201 c monitoring of treatment is needed. Vomiting \200 Leg cramps \200 i Risk of osteosarcoma seen in rats given teriparatide fo r most of their life. Black box warning in package insert. It should be avoided in patients with i ri sk of bone tumors (Paget \200\231s disease, raised alkaline phosphatase, previous skeletal radiotherapy). Male osteoporosis Osteoporosis is less common in men for the following reasons: \200 Grea ter accumulation of bone mass during growth \200 Greater bone size and strength \200 Ab sence of a distinct equivalent of menopause \200 Shorter life expectancy \200 Lesser pr opensity to fall 72-Draznin-Chap72.indd 418 4/1/2011 5:42:41 PM COMPLICATIONS OF THERAPY 419 Box 72.7 Special considerations in men \200 Secondary causes of osteoporosis are more com mon in men and need to be excluded in all men with osteoporotic fracture. \200 Bisphosphonates bene \201 t bone mass in men in a similar way to postmenopausal women. Hypogonadal men show an improvement in bone mass on testosterone replacement. This can be used as primary treatment in hypogonadal men. However , hypogonadal men respond to bisphosphonates the same as those with normal testosterone lev els. bene \201 cial in improving BMD. Parathyroid hormone SC injections have also been shown to be Box 72.8 BMD testing in males: recommendations \200 Men over the age of 50 who have suffe red a fracture or with a vertebral deformity Men with secondary causes of osteoporosis, e.g., glucocorticoids \200 Screening BMD measu res recommended for men over 70 years \200\224 \200 Ideally, male reference range to grad e risk is desirable. cost-effectiveness? Causes of increased bone mineral density Artifacts \200 Excess skeletal calcium (lumbar spondylosis, ankylosing spondylitis) \200 Extra skeletal calcium (vascular, gallstones) \200 Vertebral fracture \200 Radiodense material (surgical implants, strontium) Focal increase in bone \200 Paget \200\231s dise ase \200 Tumors (e.g., hemangioma, Hodgkins, plasmacytoma) Generalized increase in bone \200 Acquired osteosclerosis (general osteodystrophy, \202 uorosis, mastocytosis, hepatitis C, myelo \201 brosis, acromegaly) Genetic sclerosing bone dysplasias \200 d Absorption (e.g., osteopetrosis) \200 i Forma tion (e.g., sclerosteosis) \200 Disturbed balance of formation and resorption 72-Draznin-Chap72.indd 419 4/1/2011 5:42:41 PM CHAPTER 72 Osteoporosis 420 Further reading Black DM, Delmas, PD, Eastell R, et al. (2007). Once-yearly zoledronic acid for treatment of post- menopausal osteoporosis. N Engl J Med 356(18):1809 \200\2231822. Cranney A, Tugwell P, Wells G, et al. (2002). Meta-analyzes of therapies for postmenopausal oste- oporosis. I. Systematic reviews of randomized trials in osteoporosis: induction and methodology. Endocr Rev 23(4):496 \200\223507. Cummings S, San Martin J, McClung M, et al. (2009). Denosumab for prevention of fractures i n postmenopausal women with osteoporosis N Engl J Med 361:756 \200\223765. Ebeling PR (2008). Osteoporosis in men N Engl J Med 358:1474 \200\2231482. Khosla S, et al. (2008). Osteoporosis in men. Endocr Rev 29:441 \200\223464. Meunier PJ, Roux C, Seeman E, et al. (2004). The effects of strontium ranelate on the risk of verte- bral fracture in women with postmenopausal osteoporosis. N Engl J Med 350(5):459 \200\223468. National Osteoporosis Foundation: Clinician \200\231s guide to prevention and treatment of osteoporosis. Available at: http://www.nof.org/professionals/Clinicians_Guide.htm. Acessed Jan 2010. Sambrook P, Cooper C (2006). Osteoporosis. Lancet 367(9527);2010 \200\2232028. 72-Draznin-Chap72.indd 420 4/1/2011 5:42:41 PM PATHOLOGY 421 Paget \200\231s disease Paget \200\231s disease is the result of greatly i local bone turnover, which occurs partic ularly in the middle-aged or elderly. Pathology The primary abnormality in Paget \200\231s disease is gross overactivity of the o steoclasts, resulting in greatly i bone resorption. This secondarily results in i osteoblas tic activity. The new bone is laid down in a highly disor- ganized manner and leads to the characteristic pagetic abnormality, with irregular packets of woven bone being apparent on biopsy and disorgan- ized internal architecture of the bone on plain radiographs. Paget \200\231s disease can affect any bone in the skeleton but is most fre- quently found in the pelvis, vertebral column, femur, skull, and tibia. In most patients it affects sever al sites, but in about 20% of cases a single bone is affected (monostotic disease). Typically, the disease will start in one end of a long bone and spread along the bone at a rate of about 1 cm per year. Although it can spread within an affected bone, it appears tha t the pattern of disease is \201 xed by the time of clinical presentation, and it is exce edingly rare for new bones to become involved during the course of the disease. Paget \200\231s disease alters the mechanical properties of the bone. Thus, pagetic bones a re more likely to bend under normal physiological loads and liable to fracture. This can take the form of complete fractures, which tend to be trans- verse, rather than th e more common spiral fractures of long bones. More frequently, \201 ssure or incremental fractures are seen on the convex surface of bowed pagetic bones. These may be painful in th eir own right but are also liable to proceed to complete fracture. Pagetic bones are also larger than their normal counterparts. This can lead to i arthritis at adjacent joints and to pressure on nerves, producing neurological compression syndromes and, when it occurs in the skull base, sensorineural deafness. Etiology of Paget \200\231s disease The etiology is unclear. There are two major theories. Familial \200 Some genetic associations, especially with sequestomma at 18q. \200 These are not invariable. Viral \200 Inclusion bodies similar to those seen in viral infections are present in pagetic osteoclasts. 73-Draznin-Chap73.indd 421 3/31/2011 3:59:52 PM CHAPTER 73 Paget \200\231s disease 422 Some investigators have found paramyxoviral (measles or canine distemper) protein or nucleic acid in pagetic bone. Others are not able to replicate this. Epidemiology Paget \200\231s disease is present in about 2% of the UK population over the a ge of 55. Its prevalence increases with age and it is more common in men than women. Only a bout 10% of affected patients will have symptomatic disease. It is most common in the UK or in migrants of British descent in North America and Australa sia, but is rare in Africa. Recent studies in the UK and New Zealand have suggested that th e prevalence may be declining with time. Clinical features \200 90% asymptomatic \200 The most notable feature is pain. This is frequently multifactorial: i Metabolic activity of the bone \200 Changes in bone shape \200 Fissure fractures \200 Nerve compression \200 Arthritis Pagetic bones tend to increase in size or to become bowed (16% cases): bowing can be so sev ere as to interfere with function. Fractures (either complete or \201 ssure) are present in 10%. 73-Draznin-Chap73.indd 422 3/31/2011 3:59:53 PM INVESTIGATION 423 Investigation The diagnosis of Paget \200\231s disease is primarily radiological (Box 73.1) Box 73.1 Radiological features of Paget \200\231s disease Early disease \200\224primarily lytic \200 V-shaped \200\230cutting cone \200\231 in lo ng bones \200 Osteoporosis circumscripta in skull Combined phase (mixed lytic and sclerot ic) \200 Cortical thickening \200 Loss of corticomedullary distinction \200 Accentuat ed trabecular markings Late phase \200\224primarily sclerotic \200 Thickening of long bon es \200 Increase in bone size \200 Sclerosis An isotope bone scan is frequently helpful in assessing the extent of skeletal involvement with Paget \200\231s disease. It is partic ularly important to identify Paget \200\231s disease in a weight-bearing bone because of th e risk of fracture. The uptake of tracer depends on the disease activity, and iso- tope bon e scans can also be used to assess the response to therapy. In active disease, plasma alkaline phosphatase activity is usually (85%) elevated. An excep tion to this is in monostotic disease, when there may be insuf \201 cient bone involved to raise the enzyme levels above normal. Alkaline phosphatase activity responds to successful treatment. There is little advantage i n using the more modern markers of bone turnover over the total alkaline phosphatase activi ty for the monitoring of pagetic activity. A possible exception to this is in patients with liver disease, where changes in bone alkaline phosphatase might be masked by the liver iso enzyme. 73-Draznin-Chap73.indd 423 3/31/2011 3:59:53 PM CHAPTER 73 Paget \200\231s disease 424 Complications Deafness is present in up to 1/2 of cases of skull base Paget \200\231s. Othe r neu- rological complications are rare. These can include the following: \200 Compressio n of other cranial nerves with skull base disease \200 Spinal cord compression is most co mmon with involvement of the thoracic spine and is thought to result as much from a vascula r steal syndrome as from physical compression. It frequently responds to medical therapy wi thout need for surgical decompression. Platybasia, which can lead to an obstructive hydrocephalus that may require surgical drainage Osteogenic sarcoma: \200 Very rare complication of Paget \200\231s disease \200 Rarely amenable to treatment \200 Presents with i pain and radiological evidence of tumor, and a mass Any increase of pain in a patient with Paget \200\231s disease should arouse sus- pic ion of sarcomatous degeneration. A more common cause, however, is resumption of activity of disease. Pagetic sarcomas are most frequently found in the humerus or femur but can affect any bone involved with Paget \200\231s disease. 73-Draznin-Chap73.indd 424 3/31/2011 3:59:53 PM TREATMENT 425 Treatment Treatment with agents that decrease bone turnover reduces disease activ- ity as i ndicated by bone turnover markers and isotope bone scans. There is evidence to suggest that such treatment leads to the deposition of his- tologically normal bone. Although such treatment has been shown to help pain, there is little evidence that it bene \201 ts the other consequences of Paget \200\231s disease. In par- ticular, the deafness o f Paget \200\231s disease does not regress after treatment, although its progression may be halted. Nonetheless, it has become generally accepted to treat patients in the hope that future com plications of the disease will be avoided. Typical indi- cations for treatment of Paget \200\231s disease are listed in Box 73.2. The bisphosphonates have become the mainstay of treatment (Table 73.1). Calcitonin and plicamycin are no longer used. Patients should also be fully replete in both calcium and vitamin D before and during treatment. Goals of treatment \200 Normalize bone turnover \200 Alkaline phosphatase in normal ran ge \200 The more aggressive the initial therapy, the longer the disease remission. Minimize symptoms \200 Prevent long-term complications \200 No actual evidence that tre atment achieves this Box 73.2 Indications for treating Paget \200\231s disease \200 Pain \200 Neurological c omplications (e.g., deafness, spinal cord compression) \200 Disease in weight-bearing bon es \200 Prevention of long-term complications (e.g., bone deformation, osteoarthritis) \200 Young patients \200 In preparation for surgery \200 Hypercalcemi a \200 Following fracture 73-Draznin-Chap73.indd 425 3/31/2011 3:59:53 PM CHAPTER 73 Paget \200\231s disease 426 Table 73.1 Biophosphonates licensed in the U.S. for Paget \200\231s disease Duration of treatment Drug Dose Side effects 6 months Nausea Diarrhea Bone pain i Focal osteomalacia Etidronate 5 mg/kg per day orally in middle of 4-hour fast (max 400 mg) Pamidronate 3 x 60 mg IV infusion or 6 x 30 mg IV infusion 2-week interval Weekly interval In \202 uenza-like symptoms i Bone pain Iritis Risedronate 30 mg orally on rising and wait 30 minutes before breakfast 2 months Increased bone pain Nausea Tiludronate 400 mg/day and wait 2 hours before food in the morning 3 months, and 3 months post- treatment observation period Increased bone pain Nausea Zoledronic acid 5 mg IV Single dose Flu-like symptoms i Bone pain Upper GI side effects Bone pain Alendronate 40 mg orally on rising, wait 30 minutes upright before eating 6 months Monitoring therapy \200 Plasma alkaline phosphatase every 6 months \200 Clinical assess ment Re-treat if symptoms recur with objective evidence of disease recur- rence (alkaline phosph atase or positive isotope scan). If treating for asymp- tomatic disease, re-treat if alkali ne phosphatase increases 25% > nadir. Further reading Bilezikian, JP, Watts JT Jr, Fuleihan Gel-H, et al. (2002). Summary stateme nt from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 87(12):5353 \200\2235561. Davies M, Fraser WD, Hosking DJ (2002). The management of primaryhyperparathyroidism. Clin Endocrinol (Oxf) 57(2):145 \200\223155. Ralston SH, et al (2008). Pathogenous and management of Paget \200\231s disease of Core. 37 2:155 \200\223163. Selby PL, Davie MW, Ralston SH, et al. (2002). National Association for the Relief of Paget \200\231s Disease: guidelines on the management of Paget \200\231s disease of the bone. Bo ne 31(3):366 \200\223373. 73-Draznin-Chap73.indd 426 3/31/2011 3:59:53 PM OSTEOGENESIS IMPERFECTA 427 Inherited disorders of bone Osteogenesis imperfecta Osteogenesis imperfecta is an inherited form of osteoporosis in whi ch there is a genetic defect in one of the two genes ( COLIA1 and COLIA2 ) encoding the A-c hain of collagen type I collagen production. Several different mutations are recognized, and these produce differ- ent clinical pictures . These are generally separated into four and, more recently, seven different types ( b see Table 74.1).