pre-menopausal women or men under the age of 60 years, with no OSTEOPOROSIS 447 apparent cause. The female: male ratio is 10:1. Most cases are found to have \200\234low b one turnover \200\235 with low rates of bone formation. Some cases have \200\234high bone turnover \200\235 with hypercalciuria; these cases may respond to antiresorption drugs such as calcitonin and bisphosphonates. It is not clear if the majority of patients in this group will bene \201 t from therapy. For most patients with idiopathic osteoporosis, in the absence of other risk factors, the absolute risk of fracture remains low. Anticatabolic (antiresorptive) agents a re unlikely to shift the risk of fracture signi \201 cantly. Juvenile idiopathic osteoporosis ( JIO ) \200 Juvenile osteoporosis (JIO) is an uncommon disorder that occurs before or at onset of puberty. It affects the sexes equally. The cause is unknown and there are no consistent biochemical abnormalities (see Table 16.3). The child presents with pain, nontraumatic fractures around the weight-bearing joints, and collapsed vertebrae. No speci \201 c treatment is available and for most, bone mass increases to normal values as puberty progresses; however, in some cas es fractures may lead to deformity. Supportive physical therapy should be made available. \200 In the same way that height and weight charts are used to assess childhood development, there may be a role for serial bone density measurement in children with known low bone mass, as a surrogate assessment of appropriate development. Table 16.3 The causes of juvenile idiopathic osteoporosis Type Causative factor(s) Primary Calcium de \201 ciency Idiopathic Osteogenesis imperfecta Secondary Endocrine (see Table 16.2) Intestinal: malabsorption biliary atresia type I glycogen storage disease Inborn errors of metabolism \200\224homocystinuria Leukemia Congenital cyanotic heart disease CHAPTER 16 Metabolic bone diseases 448 Glucocorticoid-induced osteoporosis ( GIO ) \200 GIO is a major concern. Treatment should be offered to all patients taking prednisone for a period likely to be >3 months. The risk is present at doses as low as 2.5 mg daily, although data would suggest it increases consi derably for doses > 5mg daily. There is con \202 icting evidence about the effect of inhaled corticosteroid on fracture r isk. Patients on maximal doses of inhaled corticosteroids should be assessed for additional risk factors for osteoporosis and may require prophylaxis. The pathogenesis of GIO is controversial. Corticosteroids can affect calcium and phosphate metabolism both directly and indirectly in bone, kidney, and the intestine. Possible mechan isms are shown in Table 16.4. Primary hyperparathyroidism Primary hyperparathyroidism is a relatively common disorder wit h an adult prevalence of about 0.2% in the \201 fth to seventh decades of life. It is thr ee times more common in women than men, due to an increased incidence after the menopause. Mild hyperparathyroidism is often diagnosed after an incidental \201 nding of hypercalcem ia on routine blood tests. The manage- ment of this condition will be discussed later in th is chapter. Table 16.4 Possible pathogenesis of corticosteroid-induced osteoporosis Mechanism Site Effect Reduced bone formation Osteoblasts Reduced activity Reduced recruitment Reduced collagen synthesis Reduced growth hormone Reduced cytokine levels Adrenal \200\223testis Reduced gonadal hormones Increased bone resorption Adrenal \200\223testis Reduced gonadal hormones Parathyroid Increased PTH Intestinal Reduced calcium absorption Reduced sensitivity to vitamin D Renal Reduced calcium resorption Muscle Decreased muscle mass OSTEOPOROSIS 449 Hypogonadism \200 Hypogonadism due to any cause may lead to an increased risk of osteoporotic fracture. Causes of amenorrhea include primary ovarian failure, use of estrogen antagonists (e.g., in the management of endometriosis), hyperprolactinemia, anorex ia nervosa, and low body mass index (e.g., elite sportswomen). Causes of decreased testosterone levels include Klinefelter \200\231s syndrome, hypogonadotrophic hypogonadism, hyperprolactinemia, anorexia nervosa, and testicu lar dysfunction following mumps orchitis. Hyperthyroidism Hyperthyroidism leads to osteoporosis as a consequence of high bone turnove r, enhanced osteoclast recruitment, and increased bone resorption. Malignancy Malignant in \201 ltration and replacement of marrow tissue occurs in multiple myeloma, lymphoma, leukemia, systemic mastocytosis, and diffuse bone metastases. Mechanisms differ, for example: \200 Overproduction of osteoclast-activating cytokines (such as IL- 1 and TNF) in myeloma. Local synthesis of 1,25-hydroxyvitamin D by malignant cells in lymphoma. Overproduction of heparin, histamine, and prostaglandins that stimulate osteoclasts in mastocytosis. Other factors Potential factors that may cause generalized osteoporosis in in \202 ammator y disorders, such as RA and AS, include the systemic effects of in \202 amma- tory product s, alterations in sex hormones, altered calcium metabolism, changes in load bearing, and th e effect of drugs used in treatment. Immobilization per se leads to a net loss of bone (rat es as high as 5% per month in the \201 rst 6 months). Evaluation of osteoporosis and low-trauma fracture \200 Low-trauma fracture in those aged 50 \200\22375 years should be investigated to exclude the possibility of osteoporosis. The three most common sites of fracture are the wrist, vertebrae, and hip. Many now consider a low-trauma fracture in a person >75 years of age as strongly suggestive of osteoporosis an d would treat without measuring bone mass. Assessment and investigation for possible underl ying disease is still required. Plain radiographs are an insensitive method of assessing bone mass. The high correlation between bone mineral density (BMD) and bone strength and, therefore, b one fragility has led to the development of several techniques for assessing BMD. The standard technique for measuring BMD is dual energy X-ray absorptiometry (DEXA). It is quick, has high resolution, precision and accuracy, and can as sess the lumbar spine, femoral neck, wrist, and whole body. DEXA gives two readings, the \200\234T \200\235 and \200\234Z \200\235 scores. CHAPTER 16 Metabolic bone diseases 450 The T score is the individual \200\231s bone mineral density compared with the mean bone de nsity achieved at peak bone mass for the same sex (and, more recently, race). The Z score i s the individual \200\231s bone mineral density compared with the mean bone density for som eone of the same age and sex (and, more recently, race). Most analyzes and studies have foc used on the T score. The score is recorded as a + or \200\223 \201 gure above or below t he mean. For every one standard deviation (SD) below the mean there is a twofold increase i n the risk of fracture, i.e., an individual three SD below the mean has an eightfold risk o f fracture compared with a \200\234normal \200\235 individual of the same age, bearing in mind also that base-line risk increases with age in the \200\234normal \200\235 population . Quantitative CT allows volume measurements and can distinguish between cortical and trabecu lar bone in vertebrae. It is, however, costly and entails a high radiation exposure. Ultrasonography is a noninvasive technique that is currently being correlated with DEXA. US can be performed at the heel (calcaneus) and patella. Correlation seems poor and its role in clinical diagnostics remains unclear. Since the advent of noninvasive techniques, transiliac bone biopsy is no longer essential u nless there is the need to diagnose osteomalacia as the underlying cause. Bone biopsy may b e used as a tool in research, in particular for the quanti \201 cation of rates of bone tu rnover. Routine biochemical and hematological tests are usually normal in osteoporosis. Investigati on of the newly diagnosed osteoporotic person should include a screen for malignancy and me tabolic bone biochemical abnormalities. This at least would include an ESR, CMP, LFT, serum immunoglobulins, calcium and phosphate. Measurement of the sex hormones should also be con sidered. Biochemical markers of bone turnover are available but their precise clinical role has not been established. These include: \200 bone formation: serum bone al kaline phosphatase, osteocalcin (bone gamma carboxyglutamic acid-containing protein), type 1 procollagen peptides bone resorption: fasting urine calcium and hydroxyproline, urine collagen cross links (deox y)pyridinoline, serum tartrate-resistant acid phosphatase. These markers may be helpful in comparing \200\234high bone turnover \200\235 with \200 \234low bone turnover \200\235 cases in established osteoporosis, and in monitoring the eff ects of and compliance with treatments. Management of osteoporosis and low-trauma fractures Prevention Bone mass at any one time wi ll be determined by \200\234peak bone mass, \200\235 rate of bone loss with aging, and, wi th women, the rate and duration of postmeno- pausal bone loss. Genetic factors cannot be ma nipulated but nutritional and environmental factors may. Pharmacological intervention in at -risk individuals is good prevention practice. Currently this would include those in the ag e group 50 \200\22365 with a T score of (cid:3) \210\2223.0, or with a T score (cid:3) \210 \2222.5 with other risk factors (especially fragility fracture), and those >65 with a T sco re of (cid:3) \210\2222.5 regardless of presence of additional risk factors. OSTEOPOROSIS 451 Calcium \200 Calcium supplementation is sensible in those who have a low-calcium diet (po or in dairy products, green leafy vegetables, nuts, dried fruits, etc.). There is con \202 icting evidence about whether supplements have any effect on preventing bone loss and, the refore, risk of fracture per se in the young adult. Calcium supplementation in prepubertal children enhances the rate of change in bone mineral density but whether this translates into higher peak bone mass is unknown. In postmenopausal women, calcium supplements can lead to a reduction in the rate of decline of total-body bone mineral density. There is a role for calcium and vitamin D supplementation in the elderly osteoporotic; it c an help prevent cortical bone loss and subsequent vertebral fractures. At present the use of calcium supplements is recommended for: de \201 nite osteoporosis \200 poor calcium diet (< 400 mg intake per day) \200 supple ment to any anticatabolic (antiresorptive) treatment in the elderly. Exercise There is some evidence to suggest that physical activity decreases the rate of bon e loss around the time of menopause, although the level and type of activity remains unclea r. The activity must, however, be weight- bearing. There is little impact of exercise in im proving bone mass once osteoporotic, though it may aid in preventing further loss. Hormone replacement \200 Estrogen replacement therapy is an effective way of preventing postmenopausal bone loss. The addition of a progestogen allows endometrial shedding and min imizes the risk of hyperplasia and neoplasia. The minimum oral dose of estrogen required is 2 mg/ day, and conjugated estrogen 0.625 mg/day. Gels and transdermal/ depot treatments should be started at around 3 mg/day or 50 g/day, respectively. Evidence suggests that the use of HRT increases the risk of deep vein thrombosis, coronary artery disease, breast cancer, and stroke. These agents should therefore be used with cauti on. Treating established disease \200 Virtually all the treatments listed below have demonstr ated in the order of 40 \200\22350% reduction in risk of fragility fracture, either vertebral or at the hip in postmenopausal women with established osteoporosis. Bisphosphonates are now the most commonly used of all agents available in the treatment of established osteoporosis. They are potent inhibitors of bone resorption (anticatabolic). Cy clical disodium etidronate (400 mg daily for 2 weeks, every 3 months) is approved for use i n the Canada and Europe, but not the United States. Alendronate (10 mg daily or 70 mg weekl y), risedronate (5 mg daily or 35 mg weekly), ibandronate (2.5 mg daily or 150 mg monthly) , and zoledronate (5 mg IV yearly ) are the agents currently available. CHAPTER 16 Metabolic bone diseases 452 In general, bisphosphates are well-tolerated but should be used with caution in renal impai rment and history of esophageal re \202 ux/hiatus hernia. Symptoms of nausea and re \202 ux can be lessened by taking these medications with plenty of water and avoid lying down fo r at least 30 minutes afterwards. These agents should also be taken on an empty stomach as absorption is poor. Recent reports have identi \201 ed an association between bisphosphonates and jaw osteonecrosis, although this remains very uncommon. Long-term bisphosphonate use has also been associated with (rare) atypical fractures of the femoral shaft. Therefore, it is becoming common to stop bisphosphonate use for a year (i.e ., a \200\234drug holiday \200\235) for every 5 years of continuous use. Compliance rates with therapy are variable with reports from the United States of < 30% but reports in the United Kingdom of > 80% at 2 \200\2234 years \200 \231 duration of therapy. Calcium supplements should be taken alongside bisphosphonate therapy unless otherwise contraindicated. Calcium (800 \200\2231000 mg) and vitamin D supplements (400 \200\223800 IU) are recommende d in the elderly and those whose diet is poor in them. \200 HRT may be used as described above. Selective estrogen receptor modulators (SERMs) such as raloxifene may become more popular in the future as alternatives to HRT. Calcitonin is useful for its analgesic effect early after osteoporotic fractures. It has on ly a modest effect on bone mineral density and, therefore, is generally not used as a prima ry treatment for osteoporosis. Strontium ranelate has been shown to both increase osteoblastic bone formation and reduce osteoclastic bone resorption. Given at 2 g daily orally, studies have shown 36 \200\22341% reduction in fracture risk (hip and vertebral) against placebo. S trontium may be FDA-approved for this indication in the near future, but is not yet widely available in the United States. Furthermore, strontium, by its incorporation into bone stru cture, gives false high readings on DEXA scanning, making assessment of change in BMD follo wing therapy dif \201 cult to interpret at present. Teriparatide (20 mg SQ daily) is a parathyroid hormone analog and an anabolic agent now available for use in severe osteoporosis. It is available in a pr e- \201 lled \200\234pen \200\235 (or delivery device), and is given as a subcutaneous in jection daily for 1 year. Teriparatide should not be co-administered with bisphosphonates. Denosumab (60 mg SQ every 6 months) is a fully human monoclonal antibody that binds RANK li gand, which is necessary for osteoclast maturation. It is approved by the United States Foo d and Drug Administration for the treatment of postmenopausal women at high risk for fractu re, or patients with multiple risk factors who are intolerant of other drugs. It is importa nt to note that this drug may be associated with an increased risk of infection. OSTEOPOROSIS 453 A phase II study of ronacaleret, a calcilytic that works by blocking the calcium-sensing re ceptors on the parathyroid gland, was stopped due to lack of clinical ef \201 cacy. Acute back pain due to vertebral collapse is discussed in Chapter 20. A \202 ow chart for the management of fractures in osteoporosis is provided (see Figure 16.1). Post-menopausal women with one or more fragility fracture Age >_ 75 Age <65 Age 65 \200\22374 T-score \200\2232.5 or below confirmed by DEXA No DEXA scanning required T-score \200\2233.0 or below OR T-score \200\2232.5 or below plus 1 age \200\224 independ ent risk factor Oral bisphosphonate Contraindicated, intolerant Unsatisfactory response (e.g. further fractures despite 18 month therapy) Parathyroid hormone (teriparatide) If Strontium or SERMS T-score \200\2234 or below Or T-score \200\2233 or below with history of multiple fractur es and at least 1 age-independent risk factor Fig. 16.1 Treatment pathways for postmenopausal women with one or more fragility fracture ( based on NICE, UK guidelines 2005). CHAPTER 16 Metabolic bone diseases 454 Osteomalacia and rickets \200 Osteomalacia and rickets are characterized by defective min eralization of bone and cartilage and the accumulation of unmineralized bone matrix (osteoi d), i.e., there is, unlike osteoporosis, a decline in the ratio of mineralized bone to matr ix. Rickets is the term used for this defect in growing children before the closure of the epiphyses. There are many causes of osteomalacia but essentially they all occur due to either a de \201 ciency or resistance to vitamin D, or a non-PTH related defect in renal handling of ph osphate (see Table 16.5). \200 Both vitamin D 2 (ergocalciferol) from vegetables in the d iet, and D 3 (cholecalciferol) from animal tissues and de novo synthesis in skin, are metab olized in the liver to 25-hydroxyvitamin D and then in the kidney to 1,25-dihydroxyvitamin D 3 . The latter affects calcium metabolism by acting on the parathyroid glands (negative-f eedback loop on PTH stimulation of renal vitamin D hydroxylases), GI tract (decreased absor ption of calcium and phosphate), and bone (both bone resorption and osteoblast activation w ith bone formation). Clinical and laboratory \201 ndings \200 Classical symptoms are bone pain and tendernes s, bone deformity (depending on age of onset), and a proximal muscle weakness with a \200 \234waddling gait. \200\235 Muscle enzymes and biopsy are normal. Proximal myopathy is not a feature of X-linked hypophosphatemic rickets. The hypocalcemia of osteomalacia is usually silent but some individuals develop parasthesia s and tetany. Rarely is it severe enough to cause cardiac dysrhythmia, convulsions, or psyc hosis. Children may be hypotonic and apathetic with growth retardation and delayed walking. On weight-bearing, bones become bowed, and there is irregularity of th e metaphyseal \200\223epiphyseal junction, usually at the wrist and costochondral junctions . The latter gives rise to the feature \200\234rachitic rosary. \200\235 An indentation ma y also arise along the attachment of the diaphragm to the softened ribs (Harrison \200\231s groove). Rapid growth of the softened skull leads to craniotabes, parietal bone \202 att ening, and frontal bossing. Dentition is also delayed and poor. \200 Many bony deformitie s persist despite treatment (unless due to simple dietary de \201 ciency and treated early ) and may require surgery, e.g., tibial/ \201 bial osteotomy to correct lower limb alignme nt. The classical radiographic change of osteomalacia is the pseudo fracture (Looser \200\231s zone), found most often at the following sites: \200 ribs and clavicles \200 outer bord er of the scapulae \200 pubic rami \200 femoral neck \200 metatarsals. They appear as incomplete, radiolucent fracture lines perpendicular to the cortex, with poo r callus formation. \200 Lab tests indicative of vitamin D de \201 ciency include a low serum calcium and phosphate, elevated serum alkaline phosphatase, low OSTEOMALACIA AND RICKETS 455 Table 16.5 The classi \201 cation of osteomalacia Abnormal vitamin D metabolism Reduced availability Poor diet Inadequate exposure to sun Malabsorption Defective metabolism Hepatobiliary disease Chronic renal failure Anticonvulsant drugs Vitamin D-dependent rickets type I X-linked hypophosphatemia Oncogenic hypophosphatemia Receptor defects Vitamin D-dependent rickets type II Altered phosphate homeostasis Malabsorption Renal phosphate loss X-linked hypophosphatemia Fanconi syndrome Defective mineralization Aluminum and \202 uoride toxicity Bisphosphonate toxicity Hypophosphatasia Fibrogenous imperfecta ossium urinary phosphate and low urinary calcium excretion, low levels of 25-hydroxyvitamin D, and a mild secondary hyperparathyroidism. The latter may cause a mild hyperchloremic acidosis due to renal bicarbonate loss. Severe acidosis suggests a renal tubular defect (see Feature s and Treatment of Altered Phosphate Homeostasis, later in this chapter). Levels of 1,25-dihydroxyvitamin D may be normal and are, therefore, not helpful. If the ser um calcium and 25-hydroxyvitamin D levels are normal as well, then the defect is likely to be renal handling of phosphate or end-organ resistance. If doubt remains as to the diagnosi s of osteomalacia, a transiliac bone biopsy can be taken. Features and treatment of abnormal vitamin D metabolism \200 Vitamin D de \201 ciency th rough poor diet intake is rare unless combined with exposure to sunlight. It is a phenomeno n seen most often in the housebound elderly, and in immigrant Asian populations. Bone pain and muscle weakness respond quickly to replacement therapy, though laboratory and radiological features may take longer to return to normal. L imb deformity can be prevented if simple vitamin D de \201 ciency is treated early. Vitami n D 2 (ergocalciferol) at physiological doses of 200 \200\223400 IU/day (5 \200\22310 mg) d aily can prevent CHAPTER 16 Metabolic bone diseases 456 disease. In severe disease, a loading dose of ergocalciferol 50,000 IU can be administered weekly for 4 \200\2238 weeks. Intestinal disorders that lead to fat malabsorption can cause vitamin D de \201 ciency, as vitamin D is fat-soluble. Cortical bone loss is usually irreversible in this group. Preven tion of further damage is best achieved by annually monitoring levels of serum 25-hydroxyvi tamin D and, if levels are low-to-normal or less, replacement with ergocalciferol or calcit riol and calcium. Calcium should be supplemented at doses of 800 \200\2231000 mg/day for ad ults. Chronic renal failure and renal osteodystrophy are discussed in the section on parathyroid disease and related disorders later in this chapter. Essentially two problems arise as a co nsequence of renal failure: (1) a decline in production of 1,25-dihydroxyvitamin D, and (2) poor phosphate excretion and subsequent hyperphosphatemia. The latter worsens hypocalcemia that in turn leads to parathyroid hyperplasia and secondary hyperparathyroidism. Type I vitamin D-dependent rickets is a rare autosomal recessive disease. Defective 25-hydroxyvitamin D 1 hydroxylase enzyme activity leads to low levels of 1,25-vitamin D. Children are often affected with rickets before the age of 2 years, and fa il to respond to normal levels of vitamin D replacement. Treatment is most effective with p hysiological doses of calcitriol. Type II vitamin D-dependent rickets is a rare receptor defect disorder. About 70% of patients will have alopecia and this is an important prognostic feature when d iscussing likely outcome of treatment. In patients with normal hair, a remission can be ach ieved with high doses of vitamin D (as above). In patients with alopecia a tenfold increase in vitamin D dosing is often required and about 50% will not respond. Features and treatment of altered phosphate homeostasis \200 Osteomalacia from phosphate depletion is rare and usually occurs as a consequence of abuse of phosphate-binding antacid s over many years. Histologically it appears the same as vitamin D de \201 ciency, althoug h biochemically serum calcium is usually normal and vitamin D is high. Treatment is with ph osphate supplements and avoidance of antacids. X-linked hypophosphatemic rickets (also known as familial hypophosphatemic rickets) is a disorder of vitamin D resistance. It is important to diagnos e early as treatment can prevent deformity. It manifests itself as short stature and ricket s in the homozygous men, with variable growth and expression of bone deformity in women. De ntal delay occurs but dentition is usually normal. Proximal myopathy is not a feature of th is condition. Laboratory tests show a low serum phosphate, normal serum calcium and PTH, an d a low/ normal 1,25-dihydroxyvitamin D. Urine phosphate excretion is increased in the abse nce of abnormal acidi \201 cation, glycosuria, or aminoaciduria. A combination of calcitri ol (0.125 \200\2231.5 g/day) and phosphate (25 mg/kg/day in infants, and 1 \200\2233 g el emental phosphorus in adults) is the most effective therapy. The induction of hypercalcemia is a risk and the serum calcium should be monitored regularly every OSTEOMALACIA AND RICKETS 457 2 weeks for a couple of months on induction of therapy and thereafter approximately every 3 months. Renal tubular acidosis (RTA) and Fanconi syndrome may be associated with osteomalacia and rickets. In RTA there is a disorder of bicarbonate handlin g leading to low plasma bicarbonate, metabolic acidosis, and an inappropriate urine pH. Typ e I, distal tubular RTA occurs as a result of failure to secrete hydrogen ions (see Table 1 6.6). \200 Type II, proximal RTA is a consequence of bicarbonate wasting. Type II is ofte n associated with Fanconi syndrome. The development of rickets in both forms of RTA is due to hypophosphatemia. The acidosis should be treated and vitamin D supplements given. Fanconi syndrome is associated with a number of acquired and inherited disorders. These include multiple myeloma, amyloidosis, heavy metal toxicity and disorders of carbohydrate metabolism. The net effect of the proximal renal tubular defects is glycosuria, aminoaciduria, phosphaturia, and hypophosphatemia. Treatment of the bone dis ease is with phosphate and calcitriol supplements. Oncogenic hypophosphatemic osteomalacia is a phenomenon seen with some tumors (usually mese nchymal). The proposed mechanism is the production of a humoral factor that affects proxima l renal tubular handling of phosphate. The bone disease regresses after removal of the tumo r. A similar condition occurs in \201 brous dysplasia and neuro \201 bromatosis. Treatme nt involves phosphate and calcitriol supplements. Table 16.6 Some causes of type I, distal RTA Hereditary Primary Renal Medullary sponge Polycystic kidney Fructose intolerance Ehlers-Danlos syndrome Acquired Rheumatic SLE Sj gren \200\231s syndrome Sarcoidosis Renal Obstruction Pyelonephritis Transplantation Endocrine Hyper/hypothyroidism Hyperparathyroidism Hyperprolactinaemia Hepatic Chronic active hepatitis Liver cirrhosis Tuberculosis Lithium toxicity Cryoglobulinemia CHAPTER 16 Metabolic bone diseases 458 Parathyroid disease and related disorders This section will discuss hypercalcemia in adults and children and its rela- tion to musculoskeletal disorders. Hyper- and hypoparathyroidis m, and renal osteodystrophy are considered. For further information on vitamin D and phosph ate imbalance the reader is referred to the previous section on osteomalacia and rickets. Hypercalcemia \200 The clinical picture of hypercalcemia can range from the asymptomatic to an acute medical emergency. Calcium plasma concentrations are normally balanced between the homeostatic mechanisms oper ating in the gut, skeleton, kidneys, and extracellular \202 uids. Hypercalcemia arises mo st often as a result of excessive loss of calcium from bone but may also occur due to exces sive gut absorption. The excessive bone loss combined with a failure of the kidneys to hand le high loads of calcium, and a failure of bone to reclaim minerals quickly enough, leads t o the imbalance. Accelerated bone loss (osteoclast stimulation) may be driven by several ca uses including parathyroid hormone (PTH) and cytokines interleukin-1 (IL-1), TNF, and trans forming growth factor (TGF). PTH also induces calcium reabsortion from the kidneys. The clinical presentation of moderate to severe hypercalcemia includes: \200 joint, bone, muscle pain \200 muscle weakness \200 dehydration and pol yuria \200 lethargy \200 fatigue \200 acute confusional state \200\224unconsciousness \200 abdominal pains and vomiting \200 renal colic pains \200 electrocardiogram \201 ndings \200\224short QT interval, etc. Hyperparathyroidism and malignancy are the most common causes of hypercalcemia, accounting for 90% of all cases. A thorough history and examination is required when considering the c ause of serum calcium (see Table 16.7). Treatment options depend on the level of serum calcium, the presence of symptoms, renal impairment, and the underlying cause. For example, borderline h igh serum calcium in an asymptomatic individual with a mildly elevated PTH may simply warra nt observation in the absence of renal impairment or vitamin D de \201 ciency. On the othe r hand an individual with severe hypercalcemia, dehydration, and renal impairment due to a treatable malignancy would require urgent aggressive management. Dehydration is very common. Early rehydration is very important and often given for 24 \200 \22348 h prior to review of serum calcium levels and the instigation of further therapies s uch as bisphosphonates and loop diuretics (see Table 16.8). PARATHYROID DISEASE AND RELATED DISORDERS 459 Table 16.7 Some cause of hypercalcemia Common Primary hyperparathyroidism Malignancy Lytic metastases: TNF, IL-1 Ectopic PTH and TGF- A Ectopic 1,25 vitamin D Uncommon/ rare Drugs Thiazide diuretics Lithium Aminophylline Granuloma Sarcoidosis Tuberculosis Histoplasmosis Endocrine/ metabolic Thyrotoxicosis Pheochromocytoma Excess vitamin A or D Renal failure Immobilization Table 16.8 Treatment of hypercalcemia General principles Rehydrate with normal saline 4 liters in 24 h if needed Correct hypokalemia and hypomagnesemia Mild metabolic acidosis need not be treated Speci \201 c treatment Loop diuretics when hydrated Bisphosphonates (pamidronate) Calcitonin Glucocorticoids (hematologic malignancies and granulomatous diseases) Hypercalcemia in infancy and childhood \200 Chronic hypercalcemia of infancy may not be a ssociated with the more common clinical features mentioned earlier. More often there is a f ailure to thrive, abdominal pain, and irritability. Acute hypercalcemia is very rare in chi ldren. Conditions to consider are listed in Table 16.9. CHAPTER 16 Metabolic bone diseases 460 Table 16.9 Conditions that may be responsible for hypercalcemia in infancy and childhood Williams \200\231 syndrome A spectrum of aortic valve stenosis and facial dysmorphism ( \200\234el \201 n \200\235 fa cies). Radioulnar synostosis impedes growth in 25% of cases. There is a deletion of the elastin ge ne on chromosome 7; pathogenesis otherwise is unknown Idiopathic infantile hypercalcemia Similar milder appearance to Williams \200\231 syndrome can be seen. There are also feature s of inguinal hernias, hypertension, strabismus, and kyphosis Familial hypocalciuric hypercalcemia See later in this section Neonatal primary hyperparathyroidism Other Fat necrosis Sarcoidosis Jansen syndrome (metaphyseal dysplasia) Overdosing of milk/vitamin D Parathyroid disorders Primary hyperparathyroidism \200 Primary hyperparathyroidism (HPT) is a relatively common condition with an incidence of 1 in 1,000. It occurs at all ages tho ugh is much more common after the age of 60 with a female to male ratio of 3:1. It is unusu al in childhood and should raise the possibility of familial multiple endocrine neoplasia ( MEN) type I or type II. A single benign adenoma accounts for 80% of cases of primary HPT. Generalized gland hyperplasia accounts for 15 \200\22320% of cases. Parathyroid carcin oma is very rare. The condition is associated with bone, renal, GI, and neuromuscular complications. Bony pro blems can be seen on plain radiographs and range from mild subperiosteal bone resorption to full osteitis \201 brosa cystica with bone cysts, \200\234brown tumors, \200\235 bone r esorption of the distal phalanges and clavicles, patchy osteosclerosis (classic \200\234ru gger (rugby) jersey \200\235 spine), and multiple lytic lesions of the skull. These changes may often, however, be nonspeci \201 c. Renal stones are a common complication. GI manifestations include peptic ulceration and pancreatitis. The myopathy of primary PT is rare and more often a syn drome of fatigue and weakness is seen. \200 Primary HPT is diagnosed by assaying PTH leve ls. The assays are sensitive and able to distinguish between nonparathyroid tumor secreting PTH and parathyroid hormone. PARATHYROID DISEASE AND RELATED DISORDERS 461 Treatment \200 Medical management includes adequate rehydration and avoidance of high cal cium intake. Clinical trials with calcimimetic agents (stimulate calcium receptors with con sequent inhibition of PTH secretion) and in particular cinacalcet hydrochloride are ongoing and may be effective in primary HPT. At the time of writing, cinacalcet has received FDA a pproval for the treatment of secondary HPT in patients with chronic kidney disease. Some individuals (especially the elderly) have physiological mild elevation of PTH due to vitamin D de \201 ciency with normal calcium levels. Vitamin D sho uld be replaced and the serum calcium and PTH levels monitored after 8 \200\22310 weeks. Parathyroidectomy should be offered to individuals with moderate- to-high serum calcium and /or symptoms and complications of the condition, the latter regardless of whether serum cal cium levels are \200\234borderline \200\235 raised or not. US imaging, thallium/technetium scans, MR and CT are all useful ways of establishing the position of an adenoma. However, exploration by an experienced surgeon is equally effective. Secondary and tertiary hyperparathyroidism Secondary hyperparathyroidism occurs as a conseq uence of abnormalities in serum calcium and homeostatic \200\234sensing \200\235 of calciu m levels. With time, PTH secretion becomes autonomous and the abnormality is then called te rtiary hyperparathyroidism. This is most often seen in conditions such as end-organ renal d isease and vitamin D resistance. Calcimimetics may have an important role to play in contro lling secondary HPT but at present parathyroidectomy is the best treatment option. Vitamin D replacement to lower PTH secretion does not appear to be effective in patients with other wise normal vitamin D levels. Familial hypocalciuric hypercalcemia (FHH) or familial benign hypercalcemia (FBH) \200 Th is condition is common but most often asymptomatic. It is inherited as an autosomal dominan t with high penetrance. Radiographs, PTH, and renal function are usually normal. Although p arathyroid gland hyperplasia occurs, parathyroidectomy is invariably unsuccessful at loweri ng serum calcium levels. The two indications for parathyroidectomy are neonatal severe hyperparathyroidism and adult relapsing pancreatitis. Use of diuretics, estrogens, or phosphate to regulate serum calciu m has been unsuccessful. Patients should, therefore, be followed without intervention unles s complications arise. In pregnancy the three situations to be aware of are: asymptomatic hypercalcemia in the affected offspring of a carrier \200 severe neonatal hy percalcemia in affected offspring of an unaffected mother (intrauterine secondary hyperpara thyroidism, which usually resolves spontaneously) hypocalcemia in the unaffected offspring of an affected mother (fetal parathyroid suppression). CHAPTER 16 Metabolic bone diseases 462 Familial hyperparathyroid syndromes Up to 10% of cases of hyperparathyroidism may have a he reditary syn- drome. The most common of these is multiple endocrine neoplasia (MEN). Type I , autosomal dominant and equal in both sexes, is associated with pancreatic and pituitary a denomas, and adrenal hyperplasia. Type IIA, autosomal dominant Sipple \200\231s disease, is characterized by pheochromocy- tomas and medullary carcinoma of the thyroid. Parathyroid hormone resistant syndromes \200 Pseudohypoparathyroidism (PHP) occurs as a r esult of resistance to PTH by target tissues. The biochemical consequences are hypocalcemia , hyperphosphatemia, and elevated PTH. Cyclic AMP (cAMP) mediates many actions of PTH. Administration of bioactive PTH to normal i ndividuals leads to increased urinary excretion of cAMP. The abnormal response to this test in individuals with PHP classi \201 es them either type I \200\224no increase in urine cA MP with bioactive PTH \200\224or type II \200\224normal increase in urine cAMP but abnormal phosphate handling. The net effect is features similar to those of hypoparathyroidism of any cause (such as con genital parathyroid absence, or surgical removal). Common symptoms include: neuromuscular irritability (due to associated hypocalcaemia) \200 muscle cramps \200 ps eudopapilledema \200 extrapyramidal signs \200 mental retardation \200 cataracts \200 coarse hair/alopecia \200 abnormal dentition \200 personality disturbance. PHP type Ia (Albright \200\231s hereditary osteodystrophy (AHO)) manifests as short stature, round facies, obesity, brachydactyly, and subcutaneous ossi \201 cation. Albright observed that some individuals have these features without PHP. The term pseudops eudohypoparathyroidism was coined. This group has a normal serum calcium and PTH/ cAMP test . Cases with PHP type I but who lack features of AHO are classi \201 ed type Ib. They often have the skeletal abnormalities seen in cases of hypoparathyroidism. In type II PHP there is a normal cAMP response but an abnormal phosphate response in the kidney. The mainstay of therapy is the maintenance of serum calcium and phosphate levels. The complication of calcium and vitamin D supplements is the increase d risk of renal stones due to hypercalciuria. One gram a day of calcium is recommended and products rich in phosphate (e.g., dairy foods) should be avoided. Hydroxyvitamin D suppleme nts are valuable but serum calcium and phosphate levels should be checked weekly for 4 \200 \2236 weeks up to steady state and then every 3 \200\2236 months. PARATHYROID DISEASE AND RELATED DISORDERS 463 Renal osteodystrophy \200 The kidneys regulate calcium/phosphate balance, are a target organ for PTH, and produce 1,25-dihydroxyvitamin D (calcitriol). Renal osteodystrophy is th e net effect on bone that occurs due to derangement of calcium homeostasis in chronic renal failure. Renal bone disease is classi \201 ed as \200\230high turnover \200\231 or \200 \230low turnover \200\231 depending on whether serum PTH levels are high or low/normal resp ectively. Low turnover, adynamic osteodystrophy, is related to excess bone aluminum deposit ion in dialysis patients and is also seen in diabetes mellitus and corticosteroid therapy a nd as part of aging. Hyperphosphatemia, hypocalcemia, impaired calcitriol production, and skeletal resistance to PTH all contribute to secondary HPT in chronic renal failure. Serum PTH varies too widely in the condition to be useful in assessing treatment. Serum alkaline phosphatase is increas ed and is a useful marker though it does not distinguish between high and low turnover stat es. The clinical manifestations of renal osteodystrophy are shown in Table 16.10. Table 16.10 The clinical manifestations of renal osteodystrophy Clinical feature Comment Bone pain Common Skeletal deformity Common. Affects appendicular and axial skeleton Children: onset <3 years, rachitic; onset <10 years, bowing of long bones, widened metaphys es, pseudoclubbing, slipped epiphyses Adults: lumbar scoliosis, kyphosis, distorted thorax Growth retardation