over 20 minutes, but creatinine clearance should be above 35 mL/min Calcium falls within 12 hours nadix 4 \200\2237 days \200 Remains normal for 1 \200\2233 weeks. IV bisphosphonate therapy is generally well tolerated, but a minority of patient may develo p i bone pain or a transient pyrexia and \202 u-like symptoms. Rarer complications includ e rashes and iritis. Bisphosphonates have been associated with deterioration in renal function. For this reason, they should not be given to patients until ade- quate rehydration has been administered. I n addition, dose reduction should be considered for patients with GFR <30 mL/min. 3. Treatment of resistant hypercalcemia Although most patients will respond to IV bisphosph onates, not all will do so. In such cases, treatment with calcitonin may be helpful. This i s usually given as salmon calcitonin and may need to be given as high doses of up to 400 IU by IM injection every 6 hours. In addition to the large volume of injection required, this is frequently poorly tolerated, with side effects such as \202 ushing and nausea. Some cases of resistant hypercalcemia will respond to corticosteroid therapy, which needs t o be given in high doses, such as prednisolone 40 mg daily. 68-Draznin-Chap68.indd 386 3/31/2011 3:48:36 PM VITAMIN D INTOXICATION 387 Familial hypocalciuric hypercalcemia (FHH) FHH is also known as familial benign hypercalcem ia. \200 2% of all asymptomatic hypercalcemia \200 Autosomal dominant with virtually co mplete penetrance \200 Mutation occurs in the calcium-sensing receptor that reduces its s ensitivity such that the body behaves as if it were experiencing normocalcemia, even though the plasma calcium level is elevated. \200 Generally benign and is not usually associate d with symptoms or adverse effects such as renal stones or bone disease Does not usually show any sustained bene \201 t from parathyroidectomy \200 A few adults with FHH have had recurrent pancreatitis. In such cases, parathyroidectomy may reduce the frequency of attacks. The homozygous state produces severe life-threatening hypercalcemia soon after birth (neona tal severe hyperparathyroidism). In such cases, total parathyroidectomy is life saving. Patients have low urine calcium excretion (24 hours <2.5 mmol, fasting calcium/creatine excretion ration <0.01; b see Box 68.2 , p. 377). Further Reading Pallais JC, Kifor O, Chen YB, et al. (2004). Acquired hypocalciuric hyperca lcemia due to autoanti- bodies against the calcium-sensing receptor. N Engl J Med 351(4):36 2 \200\223369. Vitamin D intoxication The diagnosis is established by the presence of greatly elevated con centra- tions of 25OHD (>100 ng/mL) and 1,25(OH) 2 D together with suppressed PTH. If calci triol or alfacalcidol is the offending compound, then 25OHD levels will not be elevated. In mild cases, particularly when the active vitamin D metabolites are involved, the only tr eatment necessary is to withdraw the offending treatment and let the calcium levels settle. If the longer-acting vitamin D metabolites are involved, active treatment may be necessary depending on the level of increased calcium. Patients should \201 rst be stabilized with a saline infusion ( b see Box 68.4 , p. 380). Following this, the traditional management has been to give high-dose oral corticosteroids such as prednisolone 40 mg daily. This reduces the vitamin D \200\223stimulated calcium abs orption and may have bene \201 cial effects on vitamin D metabolism following intoxication . However, there is now emerging evidence to suggest that bisphospho- nates given as for hypercalcemia of malignancy are equally effective. 68-Draznin-Chap68.indd 387 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 388 Sarcoidosis Together with other granulomatous disorders, sarcoidosis causes hyper- calcemia by extrarenal production of 1,25(OH) 2 D in granulomata. This process is not under feedbac k inhibition, but is substrate regulated. The hypercalcemia is therefore dependent on vitam in D supply. Patients frequently present with hypercalcemia in the summer or fol- lowing foreign holiday s when endogenous production of vitamin D is maximal. The biochemical picture is of normal 25OHD, raised 1,25(OH) 2 D, and suppressed PTH. In add ition, other markers of sarcoid activity, such as raised angiotensin-converting enzyme (ACE ) activity, are frequently present. Treatment with high-dose corticosteroids as in vitamin D intoxication is generally recommen ded to control sarcoid activity and to minimize the GI effects of the excess 1,25(OH) 2 D. The antifungal ketoconazole and the antimalarial chloroquine (or its derivative, hydroxychl oroquine) modulate vitamin D metabolism and have been reported to reduce hypercalcemia in p atients with sarcoidosis. If the calcium levels do not respond to these, there is evidence that bisphosphonates might be useful in this situation. Further reading Bilezikian JP, Watts JT Jr, Fuleihan Gel-H, et al. (2002). Summary statemen t from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st c entury. J Clinl Endocrinol Metab 87(12):5353 \200\2235361. Palazzo FF, Sadler GP (2004). Minimally invasive parathyroidectomy. BMJ 328(7444):849 \200 \223850. Peacock M, Bilezikian JP, Klassen PS, et al. (2005). Cinacalcet hydrochloride maintains lon g-term normocalcemia in patients with primary hyperthyroidism. J Clin Endocrinol Metab 90(1 ):135 \200\223141. Stewart AE (2005). Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 35 2(4):373 \200\223379. 68-Draznin-Chap68.indd 388 3/31/2011 3:48:36 PM CAUSES 389 Hypocalcemia Causes Although hypocalcemia can result from failure of any of the mechanisms by which plas ma calcium concentration is maintained, it is usually the result of either failure of PTH s ecretion or the inability to release calcium from bone. These causes are summarized in Box 69.1. Box 69.1 Causes of hypocalcemia Hypoparathyroidism Destruction of parathyroid glands \200 Autoimmune \200 Surgical \200 Radiation \200 In \201 ltration Failure of parathyroid development \200 Isolated, e.g., X-linked \200 With other abnormalities, e.g., DiGeorge syndrome (with thymic aplasia, immunode \201 ciency, and cardiac anomalies) Failure of PTH secretion \200 Magnesium de \201 ciency \200 Overactivity of calcium se nsing receptor Failure of PTH action \200 Pseudohypoparathyroidism \200\224due to G prote in abnormality Failure of 1,25(OH) 2 D levels \200 Drugs, e.g., ketoconazole \200 Acute pancreatitis \200 Acute systemic illness Failure of release of calcium from bone Osteoma lacia \200 Vitamin D de \201 ciency \200 Vitamin D resistance \200 Renal failure Inhibition of bone resorption \200 Hypocalcemic drugs, e.g., cisplatin, calcitonin, oral phosphate, bisphosphonates, rankl inhibitors 69-Draznin-Chap69.indd 389 3/31/2011 3:47:37 PM CHAPTER 69 Hypocalcemia 390 Box 69.1 (Contd.) i Uptake of calcium into bone \200 Osteoblastic metastases (e.g., prost ate) \200 Hungry bone syndrome Complexing of calcium from the circulation \200 i Albumi n binding in alkalosis \200 Acute pancreatitis Formation of calcium soaps from autodigestion of fat \200 Abnormal PTH and vitamin D meta bolism \200 Phosphate infusion \200 Multiple blood transfusion \200\224complexing by ci trate 69-Draznin-Chap69.indd 390 3/31/2011 3:47:37 PM CLINICAL FEATURES 391 Clinical features The clinical features of hypocalcemia are largely a result of i neuromusc u- lar excitability. In order of i severity, these include the following: \200 Tingling \200\224especially of \201 ngers, toes, or lips \200 Numbness \200\224especially of \201 ngers, toes, or lips \200 Cramps \200 Carpopedal spasm \200 Stridor due to laryn gospam \200 Seizures The symptoms of hypocalcemia tend to re \202 ect the severity and r apidity of onset of the metabolic abnormality. Clinical signs of hypocalcemia depend on the demonstration of neu- romuscular irritability before this necessarily causes symptoms: \200 Chvostek \200\231s sign is elicited by tapping the facial nerve in front of the ear. A positive result is indi cated by twitching of the corner of the mouth. Slight twitching is seen in up to 15% of nor mal women, but more major involvement of the facial muscles is indicative of hypocalcemia o r hypomagnesemia. Trousseau \200\231s sign is produced by occlusion of the blood supply to the arm by in \202 ation of a sphygmomanometer cuff above arterial pressure for 3 minutes. If positive, t here will be carpopedal spasm, which may be accompanied by painful paraesthesiae. In additi on, there may be clinical signs and symptoms associated with the underlying condition: \200 Vitamin D de \201 ciency may be associated with bone pain, fractures, or proximal myopathy ( b see p. 399). Hypoparathyroidism can be accompanied by mental retardation and personality disturbances, as well as extrapyramidal signs, cataracts, and papilloedema, bas al ganglia calci \201 cation If hypocalcemia is present during development of the permanent teeth, these may show areas of enamel hypoplasia. This can be a useful physical sign indicating th at the hypocalcemia is long-standing. Pseudohypoparathyroidism \200 Resistance to parathyroid hormone action \200 Due to defe ctive signaling of PTH action via cell membrane receptor \200 Also affects TSH, LH, FSH, and GH signaling \200 Most commonly caused by autosomal dominant mutation of GNAS1 gene Signi \201 cant imprinting: Maternal transmission leads to full-blown syndrome of hormone resistance. Paternal transmission causes only phenotypic features of Albright \200\231s hereditary osteodystrophy. 69-Draznin-Chap69.indd 391 3/31/2011 3:47:37 PM CHAPTER 69 Hypocalcemia 392 Albright \200\231s hereditary osteodystrophy Patients with the most common type of pseudohy poparathyroidism (type Ia) have a characteristic set of skeletal abnormalities known as Alb right \200\231s hereditary osteodystrophy. This comprises the following: \200 Short statu re \200 Obesity \200 Round face \200 Short metacarpals Some individuals with Albright \200\231s hereditary osteodystrophy do not appear to have a disorder of calcium metabolism . In the past, the term pseudopseudohypoparathyroidism was used to describe these patients \200\231 condition. However, it is now clear that this re \202 ects different manifesta- t ions of the same underlying genetic defect as a result of imprinting. In light of the same underlying cellular abnormality, there has been a tendency to avoid th e more cumbersome designations and refer to all such patients as having Albright \200\231s hereditary osteodystrophy. 69-Draznin-Chap69.indd 392 3/31/2011 3:47:37 PM INVESTIGATION 393 Investigation \200 Plasma calcium \200 PTH \200\224presence of a low or even normal PTH concentration implies failure of PTH secretion. Serum 25 and 1-25 dihydroxy vitamin D \200 Magnesium may be needed if the patient fails t o respond. \200 Ellsworth \200\223Howard test if pseudohypoparathyroidism suspected ( b see Box 69.2 ) In chronic hypocalcemia, skull radiographs will frequently demonstrate calci \201 cation o f the basal ganglia. As this is of no clinical consequence, it is debatable whether the inv estigation can be justi \201 ed. Box 69.2 Modi \201 ed Ellsworth \200\223Howard test Method 1. Fast overnight. 2. Give 200 mL water every 30 minutes from 6 A.M. to 11 A.M. 3. F rom 8:30 A.M., collect timed 30-minute urine samples for phosphate, creatinine, and cAMP. 4. At 8:45 A.M., 10:15 A.M., and 10:45 A.M., collect blood for creatinine and phosphate. 5. At 10:00 A.M., commence 10-minute infusion of synthetic PTH 1 \200\22334, 5 units/kg to a maximum of 200 units. 6. Calculate urinary cAMP excretion as: cAMPE = [urine cAMP] \227 [plasma creatinine]/[urine creatinine] 7. Calculate tubular maximum for phosphate reabsorption: TmP/GFR = ([plasma PO 4 ] \200\223 P E )/(1 \200\223 0.01 \227 log e ([plasma PO 4 ]/P E ) where P E = [urine PO 4 ] \227 [plasma creatinine]/[urine creatinine] and all measurements are in mmol/L or using the nomogram of Walton and Bijvoet (1975; Lancet 2: 309). Interpretation \200 Patients with a normal response to PTH will demonstrate a brisk increase in cAMP excretion and a decrease in TmP. Patients with pseudohypoparathyroidism type I show neither response. There is a rarer condition, pseudohypoparathyroidism type II, in which there is a normal cAMP response but a blunted phosphaturic response. A similar pattern can be seen in some patients with profound hypocalcemia due to vitamin D de \201 ciency. It is therefore important to ensure that pat ients are vitamin D replete before undertaking a PTH infusion test. 69-Draznin-Chap69.indd 393 3/31/2011 3:47:37 PM CHAPTER 69 Hypocalcemia 394 Treatment Acute symptomatic hypocalcemia is a medical emergency and demands urgent treatmen t, whatever the cause ( bsee Box 69.3 ). Treatment of chronic hypocalcemia is more dependent on the cause. Chronic hypocalcemia Hypoparathyroidism In hypoparathyroidism the aim is not to achieve normalization of the pla sma calcium, rather to render the patient asymptomatic with a plasma calcium at or just bel ow the normal lower limit. The reason for this is that the renal retention of calcium broug ht about by PTH has been lost. Thus, any attempt to raise the plasma calcium well into the normal range is likely to result in unacceptable hypercalciuria, with the risk of nephrocal cinosis and renal stones. Box 69.3 Treatment of acute hypocalcemia \200 Patients with tetany or seizures require ur gent IV treatment with calcium gluconate (less irritant than the chloride). \200 This is a 10% w/v solution (10 mL = 2.25 mmol elemental calcium). \200 The solution should always be further diluted to minimize the risk of phlebitis or tissue damage if extravasation occurs. \200 Initially, 20 mL of 10% calci um gluconate should be diluted in 100 \200\223200 mL of 0.9% saline or 5% glucose and infused over about 10 minutes. Repeat if symptoms are not resolved. \200 Care must be taken if the patient has heart dis ease, especially if taking digoxin, as too-rapid elevation of the plasma calcium can cause arrhythmias. In such patients it is advisable to monitor the cardiac rhythm during calcium infusion. To maintain the plasma calcium, give a continuous calcium infusion: 40 mL of 10% calcium gl uconate should be added to 1 L of saline or glucose solution and infused over 24 hours. The plasma calcium should be checked regularly (not less than q6h) and the infusion rate ad justed in response to change in concentration. Failure of the plasma calcium to respond to infused calcium should raise the possibility of hypomagnesemia. This can be rapidly ascertained by plasma magnesiu m estimation and, if appropriate, a magnesium infusion commenced ( b see Treatment, p. 566) . \200 In circumstances where hypoparathyroidism could be predicted (such as block dissection of the neck), infusion of calcium gluconate in an initial dose of 50 mL 10% solution ( 11 mmmol Ca) diluted in normal saline over 24 hours should be given t o avoid postoperative hypocalcemia. This dose should be adjusted in light of regular calciu m estimations. metabolites should be substituted as above. Once oral or NG tube intake is possible, calcium and active vitamin D 69-Draznin-Chap69.indd 394 3/31/2011 3:47:37 PM TREATMENT 395 In patients with mild parathyroid dysfunction, it may be possible to achieve acceptable cal cium concentrations by using calcium supplements alone. If used in this way, these need to be given in large doses, perhaps as much as 1 g elemental calcium 3 \227 daily. Most patients will not achieve adequate control with such treatment. In those cases it is n ecessary to use vitamin D or its metabolites in pharma- cological doses to maintain plasma calcium. The more potent analogs of vitamin D, such as calcitriol or alfacalcidol, have the advantage over high- dose calciferol that it is easier to make changes in therapy in respo nse to plasma calcium levels. If hypercalcemia does occur, it settles much more quickly following withdrawal of these com pounds than ergocalciferol. The dose of vita- min D is determined by the clinical response but usually lies in the range of 0.5 \200\2232 mcg of the potent analogs daily. Hypercalcemia is the main hazard of such therapy. Plasma calcium levels must be checked fre quently after any change in therapy and no less than every 3 months while on maintenance. It is essential to ensure an adequate intake of calcium as well as vita- min D analogs. In some patients it is necessary to give calcium supple- mentation, particularly in the young. It is very rarely needed in patients aged >60 years. Pseudohypoparathyroidism The principles underlying the treatment of pseudohypoparathyroidis m are the same as those underlying hypoparathyroidism. Patients with the most common form of pseudohypoparathyroidism may have resistance to the a ction of other hormones that rely on G-protein signaling. They therefore need to be assesse d for thyroid and gonadal dysfunction (because of defective TSH or gonadotrophin action). I f these de \201 ciencies are present, they need to be treated in the conven- tional manner . Vitamin D de \201 ciency b Treatment of osteomalacia and vitamin D de \201 ciency is desc ribed on p. 399. Overactivity of calcium-sensing receptor This leads to a condition known as autosomal domin ant hypocalcalcemia. It is a benign condition in which the hypocalcemia is usually asymptom atic. Treatment should be avoided in the absence of symptoms, as eleva- tion of calcium lev els even to within the normal range may cause renal impairment. Further reading Shoback D (2008). Hypoparathyroidism N Engl J Med 359:391 \200\223403. 69-Draznin-Chap69.indd 395 3/31/2011 3:47:37 PM CHAPTER 70 Rickets and osteomalacia 396 Rickets and osteomalacia De \201 nitions Osteomalacia occurs when there is inadequate mineralization of mature bone . Rickets is a disorder of the growing skeleton in which there is inad- equate mineralizati on of bone as it is laid down at the epiphysis. In most instances, osteomalacia leads to build-up of excessive unminer- alized osteoid with in the skeleton. In rickets there is build-up of unmin- eralized osteoid in the growth plat e. This leads to the characteristic radiological appearance of rickets with widening of the growth plate and loss of de \201 nition of the ossi \201 cation centers. These two relat ed conditions may coexist. Clinical features Osteomalacia \200 Bone pain \200 Deformity \200 Fracture \200 Pro ximal myopathy (depending on the underlying cause) \200 Hypocalcemia (in vitamin D de \201 ciency) Rickets \200 Growth retardation. \200 Bone pain and fractures often occurring in unusua l locations, e.g., scapular, pubic rami Skeletal deformity Bowing of the long bones \200 Widening of the growth plates widening of the wrists, \200 \234rickety rosary \200\235 (costochondral junctions enlarged) 70-Draznin-Chap70.indd 396 3/31/2011 3:49:01 PM DIAGNOSIS 397 Diagnosis The diagnosis of osteomalacia is usually based on the appropriate bio- chemical \201 ndings ( b see Table 70.1). Most patients with osteomalacia will show no speci \201 c radiological abnormalities. The most characteristic abnormality is the Looser \200\231s zone or pseu- do-fracture. If t hese are present they are virtually pathognomonic of osteomalacia. If the diagnosis of osteomalacia remains in doubt, a bone biopsy may be necessary. This is often the only way of establishing the diagnosis in low- turnover conditions such as the to xic osteomalacias. Bone biopsy shows not only excess osteoid but also prolonged miner- alization lag time. Box 70.1 Vitamin D resistance Several different kindreds have been shown to have a defective vitamin D receptor. This is inherited as an autosomal recessive condition. It produces hypocalcemia and osteomalacia wi th elevated serum levels of 1,25(OH) 2 D. Approximately 2/3 of affected individuals have to tal alopecia. This con- dition is known as vitamin D \200\223dependent rickets type II. If alopecia is present, it is often termed type IIA, in contrast to type IIB, in which hair gr owth is normal. Treatment usually requires administration of large doses of active vitamin D metabolites, sometimes reaching doses of 60 mcg of cal- citriol daily. Box 70.2 Abnormal vitamin D metabolism Although liver disease could in theory lead to de \201 cient 25-hydroxylation of vitamin D , there is so much functional reserve that this is seldom a clinical problem. Two cases of rickets due to hereditary defects of 25-hydroxylase have been reported. The most common cause of failure of 1A-hydroxylase is renal failure. Congenital absence of this enzyme leads to a condition known as vita- min D \200\223dependent rickets type I. Thi s is inherited in an autosomal reces- sive fashion and results in profound rickets with myo pathy and enamel hypoplasia. Very large doses of calciferol are needed to heal the bone lesions, which, in contrast, wil l respond to physiological doses of alfacalcidol or calcitriol. 70-Draznin-Chap70.indd 397 3/31/2011 3:49:01 PM 7 0 D r a z n i n C h a p 3 9 8 7 0 . i n d d Table 70.1 Biochemical \201 ndings and causes of rickets and osteomalacia C H A P T E R 3 9 8 Alkaline phosphatase i i i i Ca d d d d PO4 d i d d 25OHD d N 1,25(OH) 2 D d d d i PTH i i i i Other Vitamin D de \201 ciency 7 0 R i c k e t s d GFR Renal failure VDDR type I (de \201 cient 1 ahydroxylase) N VDDR type II (de \201 cient vitamin D receptor) N a n d d i N or i X-linked hypo-phosphatemia (vitamin D resistant rickets [VDDR]) N N N o s t e o m a l a c i a N or d d i d Oncogenic N N May have aminoaciduria, proteinuria i Urine Ca Acidosis, aminoaciduria, glycosuria d d i i Phosphate depletion N d or N N N d Fanconi syndrome N N d or N N d N i N N or d N Renal tubular acidosis N N Acidosis Toxic (etidronate, \202 uoride) N N Diagnosed on biopsy N, normal. 3 / 3 1 / 2 0 1 1 3 : 4 9 : 0 1 P M VITAMIN D DEFICIENCY 399 Vitamin D de \201 ciency Causes \200 Poor sunlight exposure \200 Elderly and housebound \200 Asian women who c over their entire bodies with clothing \200 Excess sunscreen application \200 Pigmented skin \200 Poor diet (especially vegetarians) Malabsorption \200 iCatabolism of vitamin D \200 Secondary hyperparathyroidism Malabsorption \200 Post-gastrectomy \200 Enzyme-inducing drugs, e.g., phenytoin Investigation Diagnosis of vitamin D de \201 ciency is based on the characteristic biochem i- cal abnormalities ( b see Table 70.1, p. 398). Frank osteomalacia is usually associated with very low levels of 25OHD (<5 ng/mL, but this can occur at <8 ng/ml). The associated se condary hyperparathyroidism often results in normal or even elevated concentrations of 1,25 (OH) 2 D. Treatment Treatment is best given in the form of vitamin D 2 or D 3 , which will restore th e biochemistry to normal and heal the bony abnormalities. Although active metabolites of vi tamin D will heal the bony abnormalities, they will not correct underlying biochemical prob lem and are associated with i risk of hypercalcemia. In adults, treatment is given as a daily dose of ergocalciferol/cholecalcif- ero of 20 \200 \22325 mcg (800 \200\2231000 IU), which is often most easily administered in combination wi th a calcium supplement. An alternative that is particularly helpful if poor compliance is suspected is to give a si ngle large dose of 3.75 \200\2237.5 mg (150,000 \200\223300,000 IU). This is most effective ly given as a single oral dose (3 \200\2236 \227 1.25 mg tablets of ergo- calciferol/cholec alciferol), which can be supervised in the clinic. This can be repeated at 2- to 3-month in tervals depending on the dose. It is possible to give a similar dose by IM injection, but the absorption from this route is variable. Toxicity is very uncommon and doses of 10,000 IU may be needed for toxicity or above 200 ng/mL serum 25(OH) D. Following treatment, there usually is a rapid improvement of myopathy and symptoms of hypocalcemia. Bone pain frequently persists longer, and biochemical abnormalities may not settle for seve ral months. Following the onset of therapy, markers of bone turnover such as alkaline phosp hatase might even show a transient increase as the osteoid is mineralized and remodeled. Watch for hypercalcemia once osteomalacia is healed. Calcium concen- trations should be mon itored and vitamin D dosage reduced if necessary. 70-Draznin-Chap70.indd 399 3/31/2011 3:49:02 PM CHAPTER 70 Rickets and osteomalacia 400 X-linked hypophosphatemia \200 X-linked dominant genetic disorder \200 Severe rickets a nd osteomalacia \200 Mutation of an endopeptidase gene ( PHEX ) Clinical features The abnormal phosphate levels are often detected early in infancy, but sk eletal deformities are not apparent until walking commences. Typically there is severe rickets, with short stature and bony deformity. This continues in to adult life with bone pain, deformity, and fracture in the absence of treatment. Proximal myopathy is absent. Adults suffer from excessive new bone growth affecting particularly entheses and the longit udinal ligaments of the spinal canal. This can cause spinal cord compression, which may nee d surgical decompression. Oncogenic osteomalacia Certain tumors may be able to produce FGF23, which is phosphaturic. This is rare and usually occurs with mesenchymal tumors (such as heman- giopericytomas, hem angiomata, or osteoid tumors) but has also been reported with a variety of adenocarcinomas (particularly prostatic cancer) and hematological malignancies (e.g., myeloma and chronic l ymphocytic leukemia). A similar picture can be seen in some cases of neuro \201 bromatosis. Clinically, such pat ients usually present with profound myopathy as well as bone pain and fracture. Biochemically, the major abnormality is hypophosphatemia, but this is usually accompanied b y inappropriately low 1,25(OH) 2 D concentrations. In some patients, other abnormalities of renal tubular function such as glycosuria or aminoaciduria are also present. FGF 3 levels are elevated and fall with tumor removal. Tumor may be localized by PET or CT. Complete removal of tumor results in resolution of biochemical and skeletal abnormalities. If this is not possible, or if a causal tumor is not identi \201 ed, treatment with vitami n D metabolites and phosphate supple- ments (as for X-linked hypophosphatemia) may help ske letal symptoms. Fanconi syndrome The Fanconi syndrome is a combination of renal tubular defects that can re sult from several different pathologies. In particular, there is renal wast- ing of phospha te, bicarbonate, glucose, and amino acids. The combination of hypophosphatemia with renal tubular acidosis means that osteomalacia is a frequent accompaniment. This can be exac- erbated by defective 1A-hydroxylation of vitami n D to its active form. The osteomalacia is treated by correction of the relevant abnormalities. This might involve the administration of phosphate, alkali, or 1,25(OH) 2 D depending on the precise circumst ances. Further reading Carpenter TO (2003). Oncogenic osteomalacia \200\224a complex dance of fact ors. N Engl J Med 348:1705 \200\2231708. 70-Draznin-Chap70.indd 400 3/31/2011 3:49:02 PM HYPOPHOSPHATEMIA 401 Hypophosphatemia Phosphate is important for normal mineralization of bone. In the absence o f suf \201 cient phosphate, osteomalacia results. Clinically, the osteomalacia is often in distinguishable from others that are due to other causes, although there may be features th at will help distinguish the underlying cause of hypophosphatemia. In addition, phosphate is important in its own right for neuromuscu- lar function, and prof ound hypophosphatemia can be accompanied by encephalopathy, muscle weakness, and cardiomyop athy. Because phosphate is primarily an intracellular anion, a low plasma phosphate does not necessarily represent actual phosphate depletion. Several different causes of hypophosphatemia are recognized ( b see Box 70.3 ). Treatment The mainstay is phosphate replacement, usually orally in tablet form. Ideally, pa tients should receive 2 \200\2233 g of phosphate daily between meals, but this is not easy to achieve. All phosphate preparations are unpalatable and act as osmotic purgatives causin g diarrhea. Box 70.3 Causes of hypophosphatemia d Intestinal absorption \200 Phosphate-binding antaci ds \200 Malabsorption \200 Starvation or malnutrition i Renal losses \200 Hyperparath yroidism \200 Primary \200 Secondary, e.g., in vitamin D de \201 ciency \200 Renal t ubular defects \200 Fanconi syndrome \200 X-linked hypophosphatemia \200 Oncogenic os teomalacia \200 Alcohol abuse \200 Poorly controlled diabetes \200 Acidosis \200 Dr ugs \200 Diuretics \200 Corticosteroids \200 Calcitonin Shift into cells \200 Septicemia \200 Insulin treatment \200 Glucose administration \200 Salicylate poisoning 70-Draznin-Chap70.indd 401 3/31/2011 3:49:02 PM CHAPTER 70 Rickets and osteomalacia 402 Long-term administration of phosphate supplements stimulates parathy- roid activity. This c an lead to hypercalcemia, a further fall in phosphate, with worsening of the bone disease d ue to development of hyperparathy- roid bone disease, which may necessitate parathyroidecto my. To minimize parathyroid stimulation, it is usual to give one of the active metabolites of v itamin D in conjunction with phosphate. Typically, alfacal- cidol or calcitriol in a dose o f 1 \200\2233 mcg daily is used. Patients receiving such supraphysiological doses of vitamin D metabo- lites are at continue d risk of hypercalcemia and require regular monitor- ing of plasma calcium, preferably at l east every 3 months. The adequacy of calcitriol replacement can be assessed by maintaining 24-hour urinary calcium excretion at >4 \200\2236 mmol/day. In adults, the role of treatment for X-linked hypophosphatemia is prob- ably con \201 ned to symptomatic bone disease. There is little evidence that it will improve the long-term ou tcome. There has even been some evidence that treatment might accelerate new bone formation . In children, treatment is usually given in the hope of improving \201 nal height and mini mizing skeletal abnormality. The evidence that it is possible to achieve these goals is con \202 icting. 70-Draznin-Chap70.indd 402 3/31/2011 3:49:02 PM INTRODUCTION 403 Hypomagnesemia Introduction Low plasma magnesium levels are common in acutely ill patients. Clinical manif estations of this are less common. The most common clinical feature of magnesium de \201 ciency is neu- romuscular excitabili ty, which is virtually indistinguishable from that asso- ciated with hypocalcemia, which fr equently coexists. ECG abnormalities include a prolonged P-R interval and Q-T interval. The diagnosis is made by measurement of serum magnesium, with nor- mal values being 1.5 \200\2231.9 mEq/liter (1.8 \200\2232.2 mg/day), but it does not re \202 ect the major sour ce, which is intracellular. However, hypomagnesemia must be suspected if low calcium is dif \201 cult to correct. In some circumstances, the magnesium tolerance test is performed but requires a normal rena l function. The two major routes of loss are the GI tract and kidney. With magnesium de \201 ciency, PTH secretion is defective, leading to the presence or wors ening of hypocalcemia, which will not respond to treatment unless the magnesium de \201 ci ency is corrected. In magnesium depletion there is defective trans-membrane electrolyte tra nsportation. This can cause loss of intracellular potassium and of the renal tubule \200 \231s ability to retain potassium. 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