biochemical measurements in osteoporosis

7/27/2019 Biochemical Measurements in Osteoporosis

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A RE GU LA R CA SE -B AS ED SE RI ES ON PR AC TI CA L PATHOLO GY FO R GP s

The Royal College of Pathologists of AustralasiaThe Royal College of Pathologists of Australasia

A JOINT INITIATIVE OF

CONTENTS What tests to order

How to interpret them

Case studies

A RE GU LA R CA SE -B AS ED SE RI ES ON PR AC TI CA L PATHOLO GY FO R GP

CSPCommon Sense Pathology APRIL 2003


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Common Sense Pathology is a joint initiative of AustralianDoctor and the Royal College of Pathologists of

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2003 by the Royal College of Pathologists of Australasia www.rcpa.edu.auCEO Dr Debra GravesE-mail: [email protected] the views expressed are those of the authors, mod-ified by expert reviewers, they are not necessarily held bythe college.

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Professor Jeffrey Zajac (right)Department of Medicine, Austin andRepatriation Medical Centre, Heidelberg, Victoria

Associate Professor Peter Ebeling (far right)Departments of Diabetes and Endocrinology,

and Medicine, Royal Melbourne Hospital,Parkville, Victoria

Biochemical measurementsin osteoporosis

The clinical manifestation of osteoporosisThe fundamental feature of osteoporotic bone is increased skeletal fragility. Fractures are the onlyclinical feature. The bone is characterised by low mass and micro-architectual disruption. Vertebralfracture is the most common manifestation and more than 50% are asymptomatic and are diagnosedon a chest or abdominal X-ray.

Patients with osteoporosis present in one of three ways:n The patient has had a recent symptomatic vertebral or long bone fracture.n An X-ray reveals an asymptomatic fracture.n The patient is concerned about their bones because a relative or friend has had a fracture.

Biochemical and radiological assessment of these patients varies according to the clinicalpresentation, their age, underlying medical problems and current medications.

The first investigation for suspected osteoporosis should be a measurement of bone mineral density (BMD).


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Bone densitometryBone densitometry, by dual-energy X-ray absorptiometry (DXA) of axial sites, remains the gold stan-dard for diagnosing osteoporosis. It is important to realise this technique measures areal bone density,that is, it calculates density by dividing the bone sites mineral content by its area not its volume.Therefore, the unit of measurement is g/cm 2, which does not account for the third dimension of bonedepth. Areal BMD will therefore be influenced by bone size, and may appear low in shorter people withsmaller bones.

BMD measurement at the total hip site gives the best prediction of both hip and other osteoporoticfractures. It is important to exclude osteomalacia in patients with low BMD, as under-mineralisation of bone in this condition will cause the true BMD to beunderestimated.

For each standard deviation decrease in femoral neckBMD compared with age-matched controls, hip frac-ture risk is increased by a factor of 2.6. The relativerisks for spine and distal forearm fractures areincreased 2.3-fold and 1.7-fold respectively, whenBMD is measured at those sites. Each standard devia-tion decrease from the mean compared with 20-year-old controls is equivalent to a T score of 1.

Osteopaenia is diagnosed when the T score is between1 and 2.5, osteoporosis is diagnosed when the T scoreis less than 2.5, and severe osteoporosis is diagnosedwhen the T score is less than 2.5 and one or morefragility fractures are present.

The precision of BMD measurements means that in anindividual patient, a change of 3% at the spine or >5% at the proximal femur would be required to besignificant after 12 months.

In general, BMD should be repeated in 1-2 years to assessprogress.

It is inappropriate to measure BMD more than once a year inmost patients, the exception being patients where rapid bone loss

might be expected, such as post-transplantation or high-doseglucocorticoids.

Biochemical measurements in osteoporosisBiochemical assessment in patients with osteoporosis is used mostlyto detect the presence of an underlying reversible or treatable cause.Careful clinical assessment of such patients is required. Drugs thatcause osteoporosis include glucocorticoids and immunosuppressants.Underlying conditions which may cause osteoporosis or fractures areshown in table 1.

Table 1: Conditions that cancause osteoporosis

Endocrine diseaseHyperparathyroidismHyperthyroidismHypogonadismCushings disease

HyperprolactinaemiaType 1 diabetes

GI disordersGastrectomyInflammatory bowel diseaseMalabsorptionLiver disease

Transplantation andimmunosuppression

Malignancy Multiple myeloma

Explanation of T and Z scores, with

WHO thresholdsT score

T=-2.5 O s t e o p or o s i s

Osteo-paenia

M e a n + 2 S D s ( Z = + 2 )

M e a n - 2 S D s ( Z = - 2 )

P o p u l a t i o n m e a n

Age (years)

Adapted from Medical Journal of Australia 2002; 176.

N or m al

T o t a l h i p B M D ( g / c m

2

1.50

1.25

1.00

0.75

0.50

20 30 40 50 60 70 80 90

0.25


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Routine testsRoutine biochemical testing is performed to exclude these common illnesses and includes:n Urea and electrolytes.n Calcium and phosphate.n FBE/ESR.n LFT.n TSH.n Testosterone in men.n 25-hydroxy vitamin D.

Other tests which may be useful in some circumstancesMeasurement of oestradiol is less helpful in identifying hypogonadism in women than is measuringtestosterone in men. Most young women with amenorrhoea are hypogonadal and require appropri-ate assessment to find the cause of this problem.

Assessment for Cushings disease is only required if there is significant clinical suspicion. In suchpatients, a 24-hour urinary-free cortisol or 1mg overnight dexamethasone suppression test is themost useful screening assay.

Serum protein electrophoresis and urine Bence-Jones protein should be measured in patients in whom thereis a suspicion of multiple myeloma. Elderly patients, or patients with anaemia, hypercalcaemia or significant

weight loss should be included in this group. In the absence of hypercal-caemia, measurement of parathyroid hormone is usually not helpful.

Other causes of osteoporosis are usually obvious from the history,and investigation should be performed as appropriate.

Biochemical markers of bone turnover The place of bone turnover markers in the diagnosis and monitoring of treatment of osteoporosis patients is undergoing rapid change. Multiplemarkers have been identified and their use is increasing (see table 2).

However, despite widespread publicity, it is unclear what theappropriate approach should be or which is the best test.

Many specialists in this field rarely measure bone markers, other thanalkaline phosphatase, which is a reasonable measure of bone formation.

Clinical application of bone markers in osteoporosisPotential uses of biochemical bone markers in the management of osteoporosis are:n Monitoring the response to therapy.n Predicting the rate of bone loss.

Table 2: Bone markers

Bone formation markers

Osteocalcin and fragments

Total alkaline phosphatase

Bone alkaline phosphatase

Type I collagen propeptides

Procollagen type I N propeptideProcollagen type I C peptide

Bone resorption markers

Hydroxyproline

Hydroxylysine

Galactosyl hydroxylysineGlucosyl-galactosyl hydroxylysine

Pyridinoline

Deoxypyridinoline

Type I collagen telopeptides

N-terminal telopeptide

C-terminal telopeptide

C-terminal telopeptide generated by

MMPs

Bone sialoprotein

Tartrate-resistant acid phosphatase


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Major problems limiting their use are:n Although most patients with osteoporosis have increased bone resorption, bone turnover markers

may be normal. There is also a high biological variability of bone turnover markers.n Confounding effect of a recent fracture on some markers.n Lack of comparability of different types of bone markers within the reference interval and a lack of con-

sensus between laboratories.

Bone resorption markers decrease rapidly within three months of initiating treatment with ananti-resorptive agent. When markers are used, the aim of treatment is to reduce the marker to withinthe reference range. Comparing baseline measurement of a bone resorption marker with oneperformed three or six months later may indicate response to anti-resorptive therapy in conjunctionwith BMD measurements performed after 1-2 years of therapy.

Case 1A 52-year-old woman requests investigation of her bones. She had sustained a fractured ankle afterfalling two months previously. Her history reveals a low calcium intake, little exercise and a familyhistory of hip fracture in her mother. There is no clinical evidence of underlying illness and thepatient is on no medication. Her periods stopped at age 46. She experienced hot flushes for 2-3years but has had no further menopausal symptoms.

Question 1: Would a BMD scan be useful?In a postmenopausal patient with a fracture, a BMD scan will identify and measure the severity of osteoporosis, and will serve as a baseline for comparison after treatment.

Question 2: What biochemical tests should be ordered?It is important that secondary causes of osteoporosis be identified because, although uncommon, theyare treatable in most cases.

The routine tests listed on page 5 should be performed and will identify many underlying causes suchas primary hyperparathyroidism, hypercalcaemia of malignancy, chronic renal failure, thyrotoxicosis,multiple myeloma and osteomalacia.

In this patient, it is important to exclude multiple myeloma, so serum electrophoresis and urine Bence- Jones protein should also be measured.

It is likely that all of these investigations will be normal, although the alkaline phosphate may be ele-vated as a result of the patients recent fracture.

Question 3: Should oestradiol, progesterone, LH and FSH be measured?No. In a postmenopausal woman identifying that the oestradiol level is low, and LH and FSH are high,will not contribute to the diagnosis. Even in a younger woman whose periods are becoming irregular, asingle measurement of these hormones is not helpful in the diagnosis of early menopause.

Case 2A 40-year-old man presents with acute back pain after playing golf and an X-ray shows two anteriorwedge compression fractures at the thoracolumbar junction. On questioning, he has been tired andlethargic with reduced libido in the past six months.


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Question 1: Should a BMD scan be ordered?Yes. The BMD scan will confirm the presence of osteoporosis, which is likely given the presence of afracture on minor trauma. It will also act as a baseline for measuring the response to treatment.

Question 2: What biochemical tests would you order?Secondary causes of osteoporosis are more common in men. It would be important to perform the rou-tine tests listed on page 5, including total testosterone, to exclude an underlying cause.

In this patient it is also advisable to measure serum electrophoresis and urine Bence-Jones protein toexclude myeloma. The most common causes of osteoporosis in this scenario are vitamin Dinsufficiency or deficiency and hypogonadism.

Hypogonadism in men is a common, readily treatable cause of osteoporosis. However, it isunderdiagnosed. If this patients serum testosterone is low, LH and prolactin levels should be measuredto identify the cause of hypogonadism. It can be caused by various testicular insults, such as previousmumps, undescended testes as a child or pituitary disease.

Although controversial, most endocrinologists believe that little additional information would be gainedfrom routinely measuring sex-hormone-binding globulin to calculate the free-androgen index or otherindices of free-testosterone concentrations.

Question 3: Would you measure a biochemical bone turnover marker?If the other tests are normal, a serum or urine bone resorption marker would be measured, most oftenat the specialist level. If the marker was elevated it would influence the decision to pursuefurther investigations to exclude rarer causes of osteoporosis (eg, mastocytosis, HIV).

Case 3A 75-year-old woman presents after a hip fracture she sustained in a fall. She has been in a nursinghome for 12 months and could walk with a stick before her accident.

Question 1: What tests should be ordered?It would be most important to exclude vitamin D deficiency, as well as the usual routine tests and thoseto exclude myeloma.

Question 2: How do you make the diagnosis of osteomalacia?The gold standard for the diagnosis is the demonstration of increased osteoid thickness onhistological examination of an undecalcified bone biopsy, but this is rarely done in practice.

A slightly low phosphate is often the first indicator of osteomalacia, followed by a low serumcalcium, and osteomalacia should be suspected in these circumstances. However, serum calcium, phos-phate and total alkaline phosphotase levels may all be normal. Therefore, it is crucial to measure theserum 25-hydroxy vitamin D level the best measure of vitamin D stores. An extremely low levelmakes the diagnosis. Low vitamin D levels also cause muscle weakness, in addition to osteomalacia,and this increases the risk of falling.

Question 3: What is the best treatment for osteomalacia?The most common causes of osteomalacia are poor exposure to UV light in the institutionalisedelderly or pigmented individuals with or without excessive body covering and coeliac disease. Pro-viding her renal function is normal, this woman should be treated with oral calcium and vitamin D


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replacement with either cholecalciferol or ergocalciferol.

The recommended daily requirement is 600 IU per day. The dose available in Australia is relatively low 1000 IU ergocalciferol capsules and one capsule per day is the usual dose.

Question 4: When should the serum 25-hydroxy vitamin D level be repeated?It takes time to replace depleted body stores of 25-hydroxy vitamin D. This should be remeasuredabout three months after starting treatment. In this population it also will be important to monitoradherence with therapy.

Case 4A 20-year-old female with a history of an eating disorder and amenorrhoea attends for assessmentof her bones. She weighs 45kg and has a BMI of 17. She is on no medication other than occasionaldiuretics and although she considers her weight optimal, she is concerned about her bones.

Question 1: Should any investigations be performed?In some patients the psychological components of assessment and management are more significantthan biochemical derangements appropriate investigation should be performed in the context of overall management.

Bone densitometry test would be useful and, in particular, baseline measurements are important inyoung patients to assess the efficacy and need for continuing management. Biochemical assessment canbe difficult to interpret. Such patients often have multiple metabolic derangements includinghypokaelemia, hyponaetremia and abnormalities in pituitary hormones. They have low levels of oestradiol and progesterone associated with low levels of LH and FSH, indicating hypogonadotrophichypogonadism. Levels of 25-hydroxy vitamin D may be low and there may be evidence of malnutri-tion, such as anaemia, vitamin B 12 or folate deficiency and low-serum protein levels.

Question 2: How should this patients vitamin D status be assessed?The single best test for assessing vitamin D levels is 25-hydroxy vitamin D. 1, 25-hydroxy vitamin D isthe active form of vitamin D but measurement in the serum is rarely useful clinically.

Question 3: How should the patients progress be monitored?Bone density measurement at 1-2 years is the definitive approach to monitoring such a patient. In thefuture, bone turnover markers may be used in this situation, but it remains unclear as to which is theoptimal marker for use in such circumstances.

SUMMARY Osteoporosis is widespread in our community, and biochemical testing plays an important role indiagnosis and management.

A combination of careful clinical assessment, bone densitometry and standard biochemical tests isusually sufficient to allow accurate diagnosis of osteoporosis, identify underlying causes and guidemanagement. In some cases, extra targeted tests are required to exclude underlying conditions, such asmultiple myeloma.

Although it is likely that markers of bone turnover will play an increasing role in the managementof osteoporosis, at present their place is limited to complex cases of metabolic bone disease to detecthigh rates of bone turnover.

biochemical measurements in osteoporosis

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