disorders of bone and mineral other than osteoporosis

8/12/2019 Disorders of Bone and Mineral Other Than Osteoporosis

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Disorders of bone and mineral other than osteoporosis

Abstract:

Rickets in children and osteomalacia in adults are caused by undermineralisationof bone, which increases its susceptibility to bending and fracture; treatment is

with calcium, vitamin D or phosphate, depending on the specific mineral or

vitamin deficiency.

In Pagets disease, osteoclasts are overactive and produce woven or repair! bone,

which is mechanically weaker than lamellar bone; treatment is with antiresorptive

bisphosphonate drugs.

"ancers can produce bone lysis through direct spread within the skeleton or

production of endocrine parathyroid hormone#like factors; treatment is with a

bisphosphonate, plus appropriate therapy for the cancer.

"ancer can also produce hypercalcaemia if the capacity of the kidneys to e$crete

the calcium dissolved from bone is e$ceeded; treatment is with saline infusion to

increase e$cretion and a bisphosphonate.

Primary hyperparathyroidism is the other common cause of hypercalcaemia and is

usually associated with a single parathyroid adenoma; it is best treated with

parathyroidectomy.

%ypocalcaemia may result from severe decrease in calcium absorbedor lack of

parathyroid action; both are treated with calcium and vitamin D &ergocalciferol or

calcitriol'.

(hese disorders range from nutritional deficiencies to comple$ genetic and metabolic

diseases
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)one is uni*uely adapted to its dual role as a mechanical structure and an important

source of plasma calcium. It is composed of two phases+ an osteoid protein phase

comprising mostly collagen produced by osteoblasts, upon which the second, mineral

phase, comprising mainly calcium and phosphate, is deposited as crystal

&hydro$yapatite'. Defects may occur+

in the process of mineralisation of the osteoid;

in the process of bone remodelling, which is responsible for repair of bone

microfractures and the bone#related aspects of calcium homoeostasis &)o$ '; and

in the systems that regulate calcium and phosphorus homoeostasis &)o$ -'.

Rickets and osteomalacia

Aetiology

Rickets in children and osteomalacia in adults are mineralisation disorders in which the

structural integrity of bone is reduced because of a deficient supply of calcium to thegrowth plate and bone surface. Rickets is an abnormality of the growth plate and

osteomalacia an abnormality of bone. "auses include a very low dietary calcium intake,

calcium malabsorption due to a bowel disorder such as coeliac disease, and secondary

malabsorption due to vitamin D deficiency caused by lack of sunlight e$posure-&)o$ -'.

actors that reduce sunlight e$posure include infirmity, dress code, skin colour andsunlight sensitivity./(he disorder is clinically more evident in children because of their

greater calcium re*uirement for skeletal growth. Rickets and osteomalacia can also becaused by phosphate deficiency &see below'.

Clinical features

In children, decreased structural integrity of bone causes a variety of anatomical

abnormalities, including genu valgum and genu varum &)o$ /0', rachitic rosary&palpable bead#like enlargement of the costochondral 1unctions', craniotabes &areas of

softening of the skull' and thickening of the wrists and ankles caused by metaphyseal

widening. Pro$imal myopathy occurs in both children and adults, especially when

vitamin D deficiency is prominent. )one pain, often mistaken for osteoarthritis in adults,may be due to stress fractures that fail to heal &2oosers 3ones', often in the pelvis and

medial side of the femur.

Investigations

)iochemical testing should include measurement of serum levels of ionised calcium,

which may be low or normal, parathyroid hormone &P(%', which may be high &secondary

hyperparathyroidism' or normal, and vitamin D, which is generally 4 56 nmol72 &vitamin
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D insufficiency' and possibly 4 /6 nmol72 &frankly low'.80 slightly raised level of

serum alkaline phosphatase is an easily detected and relatively sensitive marker of the

mineralisation defect of osteomalacia. 9ost laboratories report total alkaline phosphataselevel, comprising both liver and bone isoen3ymes. 0lthough there are specific assays for

bone alkaline phosphatase, the diagnosis of a mineralisation defect is usually considered

when the alkaline phosphatase level is raised but other liver en3ymes are normal.%owever, as bone alkaline phosphatase levels rise with age, it is important to differentiate

pathological and physiological changes.

Management

(reatment comprises calcium supplementation combined with replacement vitamin D, ifthis is deficient. Dietary calcium is effective, but it is easier to consume the re*uired

*uantity of calcium &:- g in adults, 6.5: g in children' in tablet form, as calcium

carbonate or the better#absorbed calcium citrate.5itamin D replacement withergocalciferol &two to three 666 I< capsules daily' is appropriate even if sunlight is

available. =urprisingly, this preparation is not supported by the Pharmaceutical )enefits

=cheme. 2ower doses of vitamin D are available in many other over#the#counterpreparations. (he active form of vitamin D, calcitriol &6.-5: >g daily', is used if renal

function is compromised.

Hypophosphataemic rickets

Aetiology

Rickets and osteomalacia may also result from a deficient supply of phosphate to thegrowth plate and bone surface. 0s dietary phosphate, unlike calcium, is rarely deficient,

the cause is usually e$cess phosphate e$cretion in the urine. (he causes include a rangeof disorders of phosphate transport in the kidney+?

"hildhood#onset autosomal dominant hypophosphataemic rickets &0D%R' is

associated with activating mutations in the gene encoding fibroblast growth factor

&@#-/', which acts as a hormone to increase renal phosphate e$cretion.

A#linked hypophosphataemic rickets is associated with mutations that inactivate

the product of the P%BA gene &phosphate#regulating gene with homologies to

endopeptidase on the A chromosome'.

In adults, oncogenic osteomalacia &also known as tumour#induced osteomalacia'

is caused by benign, or occasionally malignant, mesenchymal tumours that secretefactors that lead to phosphate wasting and a phenotype similar to A#linkedhypophosphataemic rickets.

In the last two conditions, serum levels of fibroblast growth factor are also raised, but the

e$act relationships between renal tubular phosphate handling, fibroblast growth factor

and P%BA function and stability are unknown.
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)oth localised and hormone#mediated cancer#induced bone disease may present with

pain, fracture or hypercalcaemia &see below'. 2ocalised disease may also cause

paraplegia.Investigations

2ocalised disease is detected with radiological investigations, including plain $#ray, "(and 9RI scanning, as well as isotope studies if re*uired. )iochemical evaluation must

include measurement of plasma calcium and creatinine levels to detect hypercalcaemiaand potential renal dysfunction.

Management

2ytic and sclerotic bone disease is treated with monthly intravenous doses ofbisphosphonate, either pamidronate &?6:G6 mg' or 3oledronic acid &8 mg'. (his directly

inhibits osteoclast#mediated bone resorption.GIf hypercalcaemia is present, a saline

infusion is also used to increase renal calcium e$cretion &see below'. In addition to

treatment directed at the bone itself, the primary cancer and its metatases should be

treated as re*uired by localised surgery, radiotherapy, chemotherapy or endocrinetherapy.

Pagets disease of bone

Aetiology

Pagets disease is a localised disorder of osteoclast overactivity, which leads to the

formation of mechanically ineffective woven or repair! bone, rather than lamellar

bone.6(his results in bending of long bones, with compensatory periosteal e$pansionand cortical thickening &)o$ /)'. =ome variants of the disease are caused by a mutation

in the se*uestosome gene.In the past, a slow#virus origin has been postulated, perhapsassociated with close contact with dogs, but this suggestion remains controversial.-

(he disease occurs in people of northern Buropean background./(he condition is

progressive through life but does not usually cause symptoms until mid or later life &see

case report,)o$ 8'.

Clinical features

=ymptoms comprise localised deformity, bone pain and fracture, including stress fracture

&)o$ /)'. "areful e$amination of affected areas, noting deformity, temperature of the

overlying skin and localised bone pain suggestive of stress fracture are important.

Paraplegia, deafness and high output heart failure occur occasionally.Investigations

)one scanning with a radiolabelled bisphosphonate tracer of bone activity is useful to

detect foci of disease in other bones and should be used in preference to radiologicalskeletal survey. %owever, radiology is re*uired to determine the precise e$tent and

severity of the disease and to e$clude metastatic cancer.
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)iochemical evaluation is directed at measuring markers of bone formation &serum

alkaline phosphatase and osteocalcin' and resorption &urine deo$ypyridinoline to

creatinine ratio' and e$cluding other bone disorders, such as cancer, osteomalacia andhyperparathyroidism.8(he single most practically useful test for diagnosis is

measurement of serum alkaline phosphatase level, which may be very high, although

occasionally within the reference range.

Management

=ymptomatic treatment withanalgesics may be all that is re*uired. %owever, with the

development of powerful, effective and safe bisphosphonates, therapy to prevent long#

term deformity is now possible. (his can be achieved with alendronate &86 mg daily for? months', risedronate &/6 mg daily for - months' or tiludronate &866 mg daily for

/ months' as initial therapy. %owever, deformity may be best prevented by continuous

use of these drugs, rather than the intermittent use currently approved by the (herapeutic@oods 0dministration for management of Pagets disease.

Hypercalcaemia

Aetiology

0lthough there are many causes of hypercalcaemia, by far the most common are cancerand primary hyperparathyroidism. If metastatic cancer induces sufficient bone resorption,

the capacity of the kidneys to e$crete calcium is overwhelmed, and hypercalcaemia

occurs, which itself is nephroto$ic. In primary hyperparathyroidism, the raised calciumset point for P(% secretion results in inappropriately high levels of this hormone in the

setting of persistent hypercalcaemia. In most cases, the condition is associated with a

single adenoma, but in about 6H to 5H there is multiglandular hyperplasia. In humoral

hypercalcaemia of malignancy, circulating hormonal factors produced by malignanttissue, such as P(%#related peptide, induce hypercalcaemia by increasing bone resorption

and reducing renal calcium e$cretion through effects on the P(% receptor.

Clinical features

In cancer#induced hypercalcaemia, there may be symptoms of bone involvement as

outlined above. Eausea, indigestion and constipation and mental confusion are criticaladditional findings referable to the hypercalcaemia. Primary hyperparathyroidism may

present with similar but less marked symptoms, with the addition of a history of kidney

stones. ften, hypercalcaemia is identified incidentally by screening! tests. (hesepatients may have no symptoms truly referable to the hypercalcaemia.

Investigations

In primary hyperparathyroidism, plasma levels of ionised calcium and P(% are high

relative to each other and must be measured in the same sample5&see case report,)o$5'. In cancer#induced hypercalcaemia, P(% is suppressed, but P(%#related peptide levels

may be elevated.?Renal function should be measured because of the potential effect of

hypercalcaemia in reducing kidney function. )one involvement should be assessed by
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measuring markers of bone turnover, and vitamin D deficiency e$cluded, given that it

may be associated with primary hyperparathyroidism.

Management

(he acute management of hypercalcaemia is the same irrespective of its cause. It

comprises+

intravenous saline to e$pand the e$tracellular volume and obviate calcium

resorption in the pro$imal renal tubules, which accompanies a volume#contractedstate; and

intravenous bisphosphonate therapy to reduce osteoclast activity, which lowers

calcium level over about 8 days.

Diuretics should be used only if the patient becomes volume overloaded. (here is no

place for forced saline diuresis.

Definitive therapy depends on the aetiology. or e$ample, in myeloma, prednisone&86 mg daily' is effective in reducing osteoclast activity. In cancer#induced

hypercalcaemia, radiotherapy, chemotherapy or endocrine therapy may be re*uired.

Primary hyperparathyroidism is best treated by parathyroidectomy.C(he e$actindications for surgery remain controversial as there are no randomised controlled trial

data. Presurgery localisation is being re#e$amined, but an old truism is that the most

important localisation is that of an e$perienced parathyroid surgeon!. (here is no placefor the occasional parathyroidectomist!.

Hypocalcaemia

Aetiology

(he most common cause of hypocalcaemia remains hypoparathyroidism caused bysurgical removal of all parathyroid tissue, often during total thyroidectomy for cancer.

Renal failure is another common cause, and protein#losing states can result in low total

calcium levels, necessitating correction of the total calcium for the prevailing albumin

concentration. ther causes include severe vitamin D deficiency, as discussed previously,and hypomagnesaemia resulting from dietary deficiency, malabsorption or ion transport

defects in the kidney, which interferes with P(% secretion and action. 0 rare cause is

pseudohypoparathyroidism, a familial disorder of P(% end#organ action.

Clinical features

0s with hypercalcaemia, neurological symptoms are the most worrying, with epilepticfits the most dramatic. Paraesthesiae of the hands and around the mouth are more

common, although these symptoms may be induced by hyperventilation, which produces

temporary ionised hypocalcaemia due to acid:base changes. 2ong#term ectopic

calcification of the lens &cataracts' and basal ganglia may occur. (he classical signs of
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neuromuscular irritability are elicited by percussion over the facial nerve, which induces

refle$ contraction of the corner of the mouth, and by induction of forearm ischaemia with

a sphygmomanometer, which produces contraction of finger fle$ors into maindaccoucheur!.

Inestigations0 low plasma calcium level is the sine *ua non. 0 low P(% level suggests a problem in

P(% secretion caused by primary hypoparathyroidism or magnesium deficiency, while a

high P(% level suggests calcium deficiency, usually due to vitamin D deficiency, renalfailure or, occasionally, failed end#organ action.

Management

Primary hypoparathyroidism is best managed with a combination of calcium andcalcitriol, with or without a thia3ide diuretic to reduce renal calcium loss. 9anagement of

vitamin D deficiency is outlined above. If magnesium deficiency is identified

biochemically, replacement therapy with magnesium aspartate &566 mg:- g daily' is

indicated.

Renal osteodystrophy

(his comple$ form of metabolic bone disease occurs in patients with chronic renal failureand is usually managed by renal physicians. (he clinical manifestations of bone pain and

ectopic calcification occur in the dialysis phase of the illness. Barly manifestations are

secondary hyperparathyroidism and osteoporosis, which can be managed by calcium and

calcitriol supplementation.G

+ )one remodelling unit
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=ection of bone, showing a bone remodelling unit with osteoclasts &"' resorbing bone

and osteoblasts &)' laying down osteoid &', which is beginning to mineralise. &"ourtesyof Professor = tt,


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Parathyroid hormone

increases calcium release from bone

increases calcium resorption in the kidney

increases formation of calcitriol in the kidney


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increases phosphate e$cretion from the kidney

production stimulated by low calcium

production inhibited by low magnesium and high calcitriol

itamin D

increases calcium release from bone

increases calcium absorption from the intestine

increases phosphate absorption from the intestine

production stimulated by high P(% and low phosphate

Phosphatonin

increases phosphate e$cretion from the kidney

e$tracellular regulator unknown

J Parathyroid hormone &P(%' can increase both bone formation and boneresorption, depending on calcium re*uirements and blood levels. K ,-5#

Dihydro$yvitamin D/.

/+ 0natomical abnormalities in bone disorders


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0+ )owing of the tibia &genu varum' in childhood rickets, caused by poor structural

integrity of osteomalacic bone.

)+ Pagets disease of the tibia, showing typical sclerotic and lytic areas &=', thickenede$panded corte$ &"', and a stress fracture &'. =tress fractures can be very difficult to heal

and may form the site of a complete fracture.

8+ "ase report L a complication of Pagets disease

Presentation+ 0 5#year#old woman presented with pain in her tibia, which had becomecurved over some years. %er father, who was from the north of Bngland, had a similar

problem as he got older. Pagets disease was diagnosed, and treatment with a

bisphosphonate begun. %owever, the pain worsened and became localised to a tenderspot on the medial aspect of the tibia.

Investigations+ )iochemical testing showed low levels of ionised calcium &6.G5 mmol72;

reference range MRRN, .-:./- mmol72' and -5#hydro$yvitamin D &5 nmol72; RR,

O 86 nmol72', and a raised level of parathyroid hormone &.6 pmol72; RR, 6.G:G.6 pmol72'.
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Fhat is the diagnosis

(he patient has developed a stress fracture in the pagetic bone. (his has occurred

because the abnormal woven bone of Pagets disease can develop fatigue failure.

=he also has secondary hyperparathyroidism due to e$tracellular calcium

deficiency. (his can occur during therapy with bisphosphonates, as calcium is nolonger released by the overactive osteoclasts and enters pagetic bone as part of the

remineralisation process.

(he patient is also vitamin D deficient and so has reduced intestinal absorption of

calcium.

%ow should the disease be managed

(herapy with calcium &?66 mg three times daily' and ergocalciferol &-666 Imol72; RR, 56:G5 >mol72'.

Fhat was the most efficient way to diagnose the cause of the hypercalcaemia
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"areful imaging of the fracture was needed to determine whether there was

evidence of cancer metastasis.

9easurement of bone mineral density &)9D' was worthwhile at the same time to

assess the presence of osteoporosis at other skeletal sites. (his would suggest a

systemic rather than localised disorder.

0 bone scan using technetium#GGm#labelled bisphosphonate might reveal other

hot spots, suggesting metastases or fractures that would re*uire radiologicalevaluation.

)iochemical testing was the definitive test, as the plasma parathyroid hormone

level was raised at the time of the hypercalcaemia. (hese results indicate that the

patient had developed primary hyperparathyroidism, which had led to thedeterioration in renal function.

Fhat treatment should be offered

=upportive treatment and pain relief were given for the fracture. (he patient had a semi#

urgent parathyroidectomy. 0 left upper parathyroid adenoma was removed, weighing

/66 mg. %er recovery was uneventful, and creatinine level returned to its previous valueof 56 >mol72. nce the fracture had healed bisphosphonate therapy was considered.
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disorders of bone and mineral other than osteoporosis

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