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AHCPR Health Technology Assessments. Rockville (MD): Agency for Health Care Policy and Research (US); 1990-1999.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Bone Densitometry: Patients with Asymptomatic Primary Hyperparathyroidism

Health Technology Assessment, Number 6

and .

Created: .

Abstract

Bone mass loss and osteoporosis are caused by various conditions, such as asymptomatic primary hyperparathyroidism (APHPT), and treatments, such as prolonged steroid therapy. Bone densitometry is used to measure bone mass density to determine the degree of osteoporosis and fracture risk. Bone densitometers measure the radiation absorption by the skeleton to determine bone mass of the peripheral, axial, and total skeleton. Common techniques include single-photon absorptiometry (SPA) of the forearm and heel, dual-photon (DPA) and dual-energy x-ray absorptiometry (DXA) of the spine and hip, quantitative computed tomography (QCT) of the spine or forearm, and radiographic absorptiometry (RA) of the hand. Part I of this report addresses important technical considerations of bone densitometers, including radiation dose, site selection, and accuracy and precision, as well as cost and charges. Part II evaluates the clinical utility of bone densitometry in the management of patients with mild primary hyperparathyroidism. Primary hyperparathyroidism (PHPT) is a generalized disorder of calcium, phosphate, and bone metabolism due to excessive secretion of parathyroid hormone from the parathyroid gland(s). Issues addressed are the type and extent of bone loss in these patients, whether they have an increased risk for fracture, and whether parathyroidectomy reduces the risk of fracture. Subsequent assessments address the clinical utility of bone densitometry for steroid-dependent patients, estrogen-deficient women, patients with vertebral abnormalities, and end-stage renal disease patients.

Foreword

The Center for Health Care Technology (CHCT) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies. In most instances, assessments address technologies that are being reviewed for purposes of coverage by federally funded health programs.

CHCT's assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps ensure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

CHCT analyzed and synthesized data and information received from experts and the scientific literature. The results are reported in this assessment. Each assessment represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies. If an assessment has been prepared to form the basis for a coverage decision by a federally financed health care program, it serves as the Public Health Service's recommendation to that program and is disseminated widely.

CHCT is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

  • Thomas V. Holohan, M.D., FACP, Director, Center for Health Care Technology
  • Clifton R. Gaus, Sc.D., Administrator, Agency for Health Care Policy and Research

  • Questions regarding this assessment should be directed to:
  • Center for Health Care Technology
  • AHCPR
  • Willco Building, Suite 309
  • 6000 Executive Boulevard
  • Rockville, MD 20852
  • Telephone: (301) 594-4023

Part I. Technical Report

Prepared by: Martin Erlichman, M.S., and Thomas V. Holohan, M.D., FACP

Introduction

Various medical conditions such as asymptomatic primary hyperparathyroidism (APHPT) and treatments such as long-term steroid therapy and thyroid hormone replacement can result in bone mass loss and osteoporosis, which is often undetected until the person sustains a fracture. About 1.3 million fractures that occur annually in the United States in people over age 45 are ascribed to osteoporosis (1.5 million is the extrapolated value that accounts for the aging population).(1) Fractures exact an enormous toll on human disability and suffering as well as increase health care costs.

Bone densitometry is used to measure bone mass density to determine the degree of osteoporosis and fracture risk. Commonly used techniques are: single-photon absorptiometry (SPA) of the forearm and heel, dual-photon and dual-energy x-ray absorptiometry (DPA and DXA) of the spine and hip, quantitative computed tomography (QCT) of the spine or forearm, and radiographic absorptiometry (RA) of the hand.

Continuing advances in bone densitometry techniques prompted the Health Care Financing Administration (HCFA) to ask the Office of Health Technology Assessment (renamed the Center for Health Care Technology [CHCT]) to assess the effectiveness of SPA, DPA, DXA, QCT, and RA for five classes of patients. The OHTA previously assessed the general safety and effectiveness of SPA, DPA, and RA.(2-4)

Whether use of bone densitometry to document bone loss effectively alters the medical management of patients to minimize the development of osteoporosis and fractures remains controversial. The debate continues over selection of the best measurement sites and the availability of effective treatment to prevent progression of osteoporosis if significant bone loss is detected. Some concern also remains about the accuracy and precision of these techniques. These uncertainties have led to a lack of specific recommendations and protocols for bone mass testing.

The purpose of this report is to assess which techniques, if any, are clinically useful in the medical management of patients with bone loss due to APHPT. Part I of the report describes each of these techniques; part II discusses their clinical utility in the management of APHPT patients. The next four assessments in this series will assess the clinical utility of bone densitometry for steroid-dependent patients, estrogen-deficient women, patients with vertebral abnormalities, and end-stage renal disease patients.

Background

Since the 1960s, there has been a gradual development of noninvasive techniques to quantify bone mass density. Bone densitometers (absorptiometers) measure the radiation absorption by the skeleton to determine bone mass. The term "bone mass" indicates the amount of mineralized tissue in bone; the term "bone density" indicates the mass of bone defined either by length (grams per centimeter [g/cm]), area (grams per square centimeter [g/cm2]), or volume (grams per cubic centimeter [g/cm3]).

The geometric distribution of bone tissue, together with its material properties, is critical in determining the structural strength and rigidity of the whole bone. Although a variety of factors may influence bone strength and the probability of fracture, bone mass measurements are currently considered to be the most valuable objective indicator of fracture risk.(5,6)

Bone densitometers can evaluate bone density of the peripheral, axial, and total skeleton. Their clinical use is based on the assumption that bone mass is an important determinant of fractures, and that bone mass measurements may help reduce the number of fractures by identifying high-risk patients, who can then receive effective prophylaxis. Because osteoporosis is generally considered preventable but not reversible, early detection of at-risk individuals is essential.(7,8) Bone densitometry can also be used to document bone mass changes over time to monitor the course of a disease and response to therapy.

Cortical and Trabecular Bone

Factors that influence bone strength include the amount (mass), type (quality), and architecture (structure) of mineralized bone tissue. Adult bone tissue is primarily arranged either as dense cortical bone (also known as compact bone) or as a latticework of trabecular bone (also known as spongy or cancellous bone).

The combination of a smooth, dense, outer layer of compact cortical bone, together with spongy trabecular bone, provides both structural strength and an extended surface on which rapid changes in bone formation or resorption can respond to fluctuating metabolic needs. The metabolic responses of the skeleton mainly occur on trabecular bone surface.(9) Although the entire skeleton loses bone mass with aging, the distribution of bone loss is not uniform because of the different proportions of trabecular and cortical bone in the various parts of the skeleton.(10)

Osteopenia and Osteoporosis

Osteopenia refers to any condition involving reduced bone mass. Osteoporosis, a form of osteopenia, is decreased bone mass with normal bone mineralization. Bone densitometry generally has been applied to patients with bone loss associated with primary osteoporosis, which mainly occurs in postmenopausal women and the elderly. Secondary osteoporosis, which occurs in less than 5 percent of those with osteoporosis, can be a consequence of such treatment as long-term steroids or such conditions as chronic renal failure, rheumatoid arthritis, and hyperparathyroidism.

Primary osteoporosis is commonly classified as postmenopausal osteoporosis (type I) or age-related osteoporosis (type II).(11) This classification was presented by Riggs and Melton,(12) but not all investigators agree with it, and alternative proposals have been developed.(13) Type I osteoporosis occurs in a subset of postmenopausal women between the ages of 51 and 75 years, affects mainly trabecular bone, and is largely responsible for vertebral crush fractures and Colles' fractures.(14)

Type II osteoporosis is found in a large proportion of women and men over the age of 70 and results from a protracted slow phase of age-related bone loss. This condition affects twice as many women as men and is manifested mainly by hip and vertebral fractures.(12,14)

Historically, osteoporosis was recognized clinically only after fractures occurred. It was considered a syndrome consisting of both substantial bone loss and fractures.(15,16) With the development of techniques that measured bone loss before signs of radiographic change or the occurrence of fractures, osteoporosis was defined as an age-related disorder characterized by decreased bone mass and by increased susceptibility to fractures.(17)

How osteoporosis is defined is not a trivial issue. As a result of the various criteria used to define osteoporosis, estimates of its prevalence differ markedly. For example, if bone mass lower than 2 standard deviations (SD) below the mean of normal young women represents osteoporosis, then 45 percent of white women aged 50 years and older are osteoporotic.(18) A World Health Organization (WHO) study group recently defined osteoporosis as 2.5 SD below that mean, which identifies 30 percent of all postmenopausal women as osteoporotic, more than half of whom will have sustained a prior fracture.(19)

There is a growing tendency to define osteoporosis in terms of a continuum of bone density, with greatest fracture risk in those with lowest absolute density values, rather than in considering osteoporosis as a fracture/nonfracture dichotomy.(20) However, so-called "fracture thresholds" have been approximated for various skeletal sites to diagnose osteoporosis based on a level of bone mass above which nontraumatic fractures rarely occur and below which fractures are more common (e.g., 90 percent of women with vertebral fractures have spinal bone density values less than .97 g/cm2 measured by DPA).(21,22)

Other approaches include Nordin's proposal that osteoporosis be defined by identifying the normal range of bone density at specific anatomic sites in young adults and classifying bone density values less than 2 SD below the mean of this range as osteoporotic.(23) Although disagreement continues, the definition developed at the Consensus Development Conference,(24) held in Copenhagen in April 1993, is generally accepted. That conference defined osteoporosis as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.

Fractures

Although osteoporosis affects all bones, the most common so-called osteoporotic-related fractures are those involving the spine (thoracic and lumbar vertebral bodies); femur (the neck and intertrochanteric regions); and wrist (distal radius).(1) In persons over the age of 50, the incidence of these fractures increases markedly. Fractures of the distal radius, common in the middle-aged and elderly, are caused by a fall on the outstretched hand. Approximately 172,000 osteoporotic fractures occurred in the distal radius during 1985.(25) The most severe osteoporotic fracture is that of the hip, a disabling and sometimes fatal event. The prevalence of hip fractures in the United States reaches 15 percent by age 80 and exceeds 25 percent by age 90.(1) Between 250,000 and 300,000 hip fractures occur each year in the United States and the incidence may be increasing.(26-28)

However, even among elderly persons with low bone mass, most falls do not result in a fracture.(29) Greenspan et al(30) found that, in most elderly fallers with hip bone density already below the so-called fracture threshold (>2 SD lower than average peak bone mass as measured by DXA), fall characteristics and body habitus were important risk factors for hip fracture. About 90 percent of hip fractures are the result of falls, but fewer than 1 percent of falls result in hip fractures.(31)

Nevertheless, a hip fracture may often be a marker for declining health and impending death.(32) Most patients who suffer a hip fracture have severe concomitant illness. Browner et al(33) have found that diminished bone mass density is associated with increased all-cause mortality, even after excluding women with deaths resulting from fractures.

Although the true incidence of vertebral fracture is not known, more than 25 percent of all women over age 65 may have sustained a crush fracture, most of which are asymptomatic.(1) Fractures occurring at other sites, including the rib, pelvis, humerus, and proximal tibia also may be attributable to osteoporosis.(34)

Review of Available Information

Using a MEDLINE search of the National Library of Medicine data base, CHCT retrieved published articles in the English language from 1986 to 1994 addressing bone densitometry as well as its use in the diagnosis and treatment of osteoporosis related to APHPT. Text words used singularly or in combinations were osteoporosis, densitometry, absorptiometry, bone mass, bone density, measurement, bone site, precision, bone loss, biochemical markers, fracture, treatment, therapy, bone disease, APHPT, calcitonin, hormone, QCT, DXA, RA, SPA, and DPA.

The CHCT also examined the bibliographies of reviewed articles to identify publications not otherwise captured. In addition, respondents to a notice published in the Federal Register forwarded or suggested many articles. The CHCT also solicited data from other agencies of the Public Health Service (PHS).

Draft copies of the assessment were reviewed by CHCT staff and PHS officials selected by the National Institutes of Health (NIH), the Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC).

Bone Mass Measurement Techniques

Overview

Bone densitometry techniques, previously used as research tools to elucidate metabolic bone diseases, are being used with increasing frequency in clinical practice. These techniques measure radiation absorption by skeletal calcium to determine bone mass density. Single-photon absorptiometry became available in the early 1960s. It measures both cortical and trabecular bone and is limited to measuring appendicular sites such as the wrist. Dual-photon absorptiometry emits photons of two distinct wavelengths and energy levels and can scan bones in two dimensions. It became commercially available around 1980 and is most often used to measure the lumbar spine or proximal femur.

Both SPA and DPA use radioisotopes as their photon source for imaging bones. Dual-energy x-ray absorptiometry, QCT, and RA use x-ray sources. Like SPA and DPA, DXA cannot separate cortical from trabecular bone. However, it can scan an area much more rapidly and is more precise than DPA, which it is quickly replacing.(35) Although widely available, DPA devices are no longer manufactured.(36)

The advantage of QCT is its ability to separate cortical from trabecular bone with great anatomic detail. On the other hand, it is a much more difficult scan to perform and emits 100 times or more the radiation of DXA. Finally, RA is used to measure bone density in the hand.

As yet, there is no agreement on which method or methods are most clinically effective for diagnosing and monitoring the individual patient or for identifying the high-risk patient for therapeutic intervention.

The FDA has allowed SPA, DPA, DXA, and QCT to be marketed under Section 510(k) of the Medical Device Amendments of 1976 to the Federal Food, Drug, and Cosmetic Act of 1938. For QCT, approval is solely for a software package that adapts computed tomography (CT) for bone density measurements. These devices may be marketed for measurement of bone mass and for monitoring an individual patient over time. The FDA regulates RA because it considers RA a medical device. Currently, there is no FDA approval for any bone density technique that claims to predict fracture risk.

Table 1 presents a comparison of the technical features of SPA, DPA, QCT, DXA, and RA.

Table 1. Comparison of bone mass measurement techniquesa.

Table

Table 1. Comparison of bone mass measurement techniquesa.

Important differences in the characteristics and performance of these techniques include procedure charges, radiation exposure from the scan, the bone and bone site measured, and the accuracy and precision achieved. All these factors can affect the clinical utility of a given technique for managing specific patients.

Charges

Charges vary for different techniques as well as for the same technique used at different locations. Charges reported in the literature usually represent those of universities or research institutions. Smaller clinics and individual physicians not concerned with spine or hip measurements tend to install the less expensive SPA units. The more expensive DPA and now DXA units are usually installed in larger clinics, hospitals, and university settings or wherever spine or hip measurements are desired. DXA has the potential for lower costs, because DXA bone scans require much less time than QCT and DPA (which is being replaced), allowing for more patient measurements per unit of time.(37) Also, the long life of the x-ray tube results in lower maintenance costs. Computed tomography units, which are widely available, can be adapted to perform QCT bone density measurements.

Radiation dose

All bone densitometry techniques involve patient exposure to radiation. However, these techniques are generally considered to be safe, with relatively low radiation exposure to the patient. In longitudinal studies, cumulative dose becomes important. Single-photon absorptiometry, using an iodine (125I) radiation source, has the lowest dose per measurement (2-5 mrem). This dose is limited to the actual measurement sites, for example, the wrist and heel (calcaneus). Furthermore, there is no radiation-sensitive hemopoietic marrow in the calcaneus, as opposed to the vertebrae. Dual-photon absorptiometry, using gadolinium (153Gd) as the radiation source, usually delivers 5-10 mrem to the hip or spine with less than 1 mrem absorbed radiation dose at the gonads. Dual-energy x-ray absorptiometry doses are similar to those of SPA but involve exposure to the torso in the pelvic region. Quantitative CT delivers the greatest dose (100-1,000 mrem; 100-300 mrem for newer scanners). Although about equal to a chest x-ray, the QCT dose is 20-200 times that of the other techniques, with the scattered gonadal dose also proportionally higher.(5) This makes it more problematic for repeat measurements.

Site selection

Although cost and radiation exposure are considerations that may influence the choice of a measurement site, the most important consideration is the ability to indicate fracture risk. Presently, there are insufficient longitudinal data to determine if any technique or skeletal site is better than others for quantifying bone mass or measuring bone loss rates.(38) Controversy continues regarding the best choice of a bone mass measurement site for determining the extent of osteoporosis and predicting fracture risk. Some studies conclude that, to predict fracture risk in a bone, the bone density of that specific bone should be measured, and that measurements made at other parts of the skeleton have less predictive value.(39)

Conversely, others conclude that patients with vertebral fractures have generalized osteoporosis. Therefore, the measurement of spinal bone density has no predictive advantage over that of the forearm, and the risk of vertebral fracture can be predicted from appendicular sites as well as the spine (axial skeleton).(40-42) This position is supported by the results of several recent prospective studies(6,43-46) that found no convincing evidence that measurements made at the spine and hip are superior to appendicular sites for predicting subsequent fractures at the spine and hip. Yet, another study(47) concludes that low bone mass is generalized in some women and more regional in others and that those with the lowest bone mass measurements at any site are more likely to have extensive osteoporosis.

The ability to use a single-site measurement of bone density to evaluate general fracture risk at all sites has practical importance. It could eliminate the rationale for multiple-site measurements performed by some clinicians and would put less emphasis on a technique's ability to measure a particular site. Techniques not capable of bone mass measurements at the spine and/or the hip would not be eliminated from consideration for that reason. For example, measurement of appendicular sites is considered easier, costs less, and can be done with most techniques. However, vertebral sites must be measured with DXA or QCT, and these measurements can be difficult to reproduce in patients with spinal deformities and aortic calcification, artifacts that may confound the bone mass measurements. This has led some to recommend the hip, forearm (radius), and heel as alternative sampling sites.(48)

Site selection is also an issue when bone densitometry is used to monitor response to therapy, because the cortical/trabecular composition of the measurement site must reflect the effects of particular therapeutic agents.(49) For example, Mazess et al(50) consider the spine the most appropriate site for bone loss monitoring, because it shows larger decreases in bone mass at the menopause than do appendicular sites and larger increases in bone mass after estrogen-replacement therapy. However, others suggest that such a distinction may be unnecessary and that measurement of bone density by SPA or QCT of the forearm could be used for clinical followup of bone changes.(51,52)

Accuracy and precision

Measurements obtained by densitometers are compared with an independent standard measurement of bone mass, such as ashed bone sections or phantom standards calibrated against ashed bone sections.(53) The accuracy error is determined by how much the measurement varies from this accepted or "true" value. Precision error is the variability in the measurements occurring with repeated measurements of the same object.(54)

Concern has been expressed about the accuracy and precision of various techniques, particularly in the clinical setting. Single-photon absorptiometry has the greatest accuracy in vivo; DXA is considered the most precise, followed by SPA. The accuracy and precision of all the techniques can be reduced by improper patient positioning, changes in the strength of the radionuclide sources (SPA, DPA), improper calibration of the equipment, and weak quality assurance programs.

A technique's precision is critical for serial measurements that correctly document bone loss over time. A number of factors influence serial measurements, regardless of the technique chosen or site selected to determine bone mass. Attention to patient repositioning is necessary to assure that the same exact bone location is measured each time. If sequential scan locations are not matched, erroneous measurements may result, especially in regions of bone where bone mass is not uniform.

When the bone mass is expressed as an "area" density (SPA, DPA, DXA), the limb must have the same rotation and axis at each measurement so that the projected area will be the same. When the forearm, spine, hip, or heel are measured, variations in rotation or angulation of the axis will adversely affect measurements.(5)

Changes in soft tissue composition can also have significant effects on bone mass measurements. A change in soft-tissue composition surrounding the bone to be measured changes the baseline reference values against which the bone absorbance values are compared. This is true equally for RA, SPA, DPA, and DXA. For example, changes in SPA measurements may occur with treatment that alters body fat, such as anabolic steroids, norethindrone, and estrogen.(55) An increase in radial density as determined by SPA may reflect a decrease in the subcutaneous forearm fat rather than an increase in bone mass. Furthermore, the fat content of red marrow in the spine and femur changes with age and can influence absorbance. As a result, errors in QCT measurements of these sites generally increase in older patients.(5)

Changes in the strength of radionuclide sources (SPA, DPA) can significantly affect the precision of serial measurements. Serial DPA measurements can be subject to errors of up to 6 percent due to age (diminished activity) of the radionuclide source.(3,56,57) The relatively low and constantly decreasing intensity of photon sources leads to problems with long-term stability of these instruments. Instrumental instability and problems with software changes have now been recognized. Yet, it is still unclear how well certain calibration standards are able to correct for changes in radiation source intensity.(58)

The ability of densitometers to measure rates of change in bone mass depends on the magnitude of change, the precision of the method, and the number of measurements taken.(59) All five bone densitometry techniques are suitable for assessing rates of bone loss, provided that the interval between assessments is sufficiently long. If a technique has too high a precision error, its clinical utility is limited by the length of time it takes to detect significant bone loss in patients.(60,61)

The requisite minimum intervals between measurements that are necessary to reliably detect a reduction in bone mass are related to the precision attainable with current instruments and the rate of bone mass loss, assuming that the accuracy of the instrument is invariable. Table 2 illustrates the calculation of such intervals based upon published precision data, with assumed annual bone mass losses of 1-3 percent. The requisite intervals range from 1 to 17 years. However, it is unlikely that yearly densitometry would be clinically indicated given the fact that 1 percent precision error is rarely attained and that a 3 percent annual loss in bone mass would be distinctly uncommon. Precision errors in the range of 2-3 percent and annual bone mass losses of 1-2 percent are parameters more representative of published data. In those instances, the minimum interval between densitometry measures necessary to document bone mass loss would be between 3.7 and 6 years.

Table 2. Intervals required to reliably detect bone mass loss over timea.

Table

Table 2. Intervals required to reliably detect bone mass loss over timea.

Past experience with bone density measurements indicates that strict quality control, including calibration and standardization procedures, is required to maintain both precision and accuracy for reliable measurements.(56,57,62) Because differences in operator technique during scan analysis can result in large measurement variations, it is also important that a consensus be reached over procedural methods for positioning. Those who publish normal ranges should accurately describe the technique used.(63)

Even with instruments calibrated according to manufacturers' instructions, bone density values obtained by DPA and DXA imaging of spine phantoms have differed by as much as 16 percent.(49) Discrepancies in bone density measurements by different instruments appear to reflect differences in instrument design, computer algorithms, and calibration procedures.(58,64,65) For example, when comparing three DXA instruments, Arai et al(65) found each of them to be accurate when using their own standard. However, when the same lumbar spine phantom (standard) was used in each of the three systems, the bone mass density values measured by one system were 5-8 percent higher than those of the other two systems.

The calibration and standardization of bone densitometers is a complex undertaking that requires more attention because there is little agreement among manufacturers.(48,66) Although all manufacturers provide protocols for reference standards and phantom measurements, there is no industrywide agreement for one specific standard that would provide machine-to-machine comparability. Users and/or manufacturers of bone densitometers need to adopt a uniform procedure for calibrating and standardizing instruments and carry out quality control measurements using an accepted "gold standard."(49)

A report on bone mineral assessment by the National Health Technology Advisory Panel to the Australian Institute of Health recommends an accreditation policy to establish and identify quality assurance programs.(59) A review of the impact of such programs on the precision of densitometric techniques used in multicenter clinical studies shows that a 1-2 percent improvement in precision is achievable.(67)

Techniques

Single-photon absorptiometry

Single-photon absorptiometry is a noninvasive radiologic technique used to assess bone mass in the appendicular skeleton, usually the radius or calcaneus. It evaluates the amount of bone mass by measuring the transmission of gamma rays through bone. It is a simple, widely available, and relatively inexpensive measurement technique that involves minimum radiation exposure, with negligible bone marrow or gonadal radiation.(59,68)

The earliest SPA measurements were performed at the midradius, which is almost all cortical bone (approximately 95 percent). However, interest in trabecular bone mass, coupled with technical advances in SPA such as rectilinear scanning and area density measurements, provided the capability of assessing sites with greater proportions of trabecular bone: the calcaneus and distal radius.

The calcaneus is a weight-bearing bone of approximately 90-95 percent trabecular bone by volume. It is very active metabolically and may reflect the effects of age, menopause, exercise, and drugs on axial bone such as the spine.(69) Recent prospective studies show promising results for the value of calcaneus measurements in predicting fractures at peripheral as well as axial sites. However, the ability of SPA measurements at the calcaneus and radius to predict spinal bone density remains controversial.(70,71) A summary of SPA characteristics is presented in Table 3.

Table 3. Single-photon absorptiometry characteristicsa.

Table

Table 3. Single-photon absorptiometry characteristicsa.

The accuracy error of SPA measurements is determined from a calibration of the technique with the ash weight of a dried defatted human radius.(74) Calibration can also be made with standards calibrated against ashed bone sections. Single-photon absorptiometry can provide highly accurate measurements (1-3 percent error) on phantoms and bone specimens. However, accuracy errors of 3-8 percent are more common in the clinical setting.(70)

The precision error of SPA measurements is determined by repeated measurements on phantoms and patient controls. Routine clinical scans of the radius and calcaneus have a precision error of 2-5 percent, largely as a result of repositioning errors and the low and constantly decreasing intensity of the photon source.(56) Changes in SPA measurements may also occur as a result of treatment that alters body fat; a measured increase in bone density may reflect a decrease in the subcutaneous forearm fat and not a "real" gain in bone.(55) Higher precision measurements are achieved in settings with adherence to quality control and with the application of rectilinear scanning.

The short half-life (60 days) of the 125I source necessitates source changes several times a year and thus has the potential to adversely affect instrument reliability.(56) A similar device that uses an x-ray source (SXA) rather than an isotopic source is also available. The x-ray source, with its significantly greater photon output, improves the precision and the speed of the scans. Because of this and the increasing cost of 125I sources, SPA is being replaced by SXA.

More detailed descriptions of SPA may be found in the 1986 OHTA SPA assessment report by Erlichman(2) and in recent reviews by Lang et al,(72) Tothill,(75) and Wahner.(64)

Dual-photon absorptiometry

Dual-photon absorptiometry is usually used to measure bone density in the spine and hip but can also be used to quantify total body bone mass.(72) It offers no advantage over SPA for measuring appendicular bones. Unlike SPA, its energy source emits photons of two distinct energies, allowing imaging of thicker body parts.

Scanning is somewhat slow (35 minutes), but involves a low radiation dose with negligible gonadal radiation. The short half-life (253 days) of the 153Gd source necessitates changing the expensive source every 12-18 months. Dual-photon absorptiometry bone density measures reflect the total integrated mineral (cortical and trabecular) content and any extraosseous mineral in the path of the beam. Dual-photon absorptiometry scan sites and other characteristics are summarized in Table 4.

Table 4. Dual-photon absorptiometry characteristicsa.

Table

Table 4. Dual-photon absorptiometry characteristicsa.

Lumbar spine measurements by DPA are usually performed at the L2-L4 region, imaged as a planar area. Dual-photon absorptiometry measurements quantify bone mass of the entire vertebral body, including spinous processes and posterior elements, as well as calcification within surrounding tissues, for example, the aorta.(76) Abnormalities in the spine, including osteophytes, endplate hypertrophy, disc degeneration, calcified aorta, and fractures, are common in patients over 65 years of age.(76,77) These coexisting conditions may result in inaccurate and poorly reproducible vertebral measurements and have led to a preference for femoral measurements.(76,78)

Dual-photon absorptiometry measurements of the proximal femur are usually performed at the femoral neck but may also include the trochanteric region as well as a highly trabecular area called Ward's triangle.(76) There are few measurement errors attributable to artifacts in the hip region; however, the results can be affected significantly by patient positioning. Dual-photon absorptiometry computer software that does not compensate adequately for the wide variation in the anatomy of the femoral neck and adjacent soft tissues also contributes to inaccurate measurements.

The accuracy error of dual-photon absorptiometry measurements is established by scanning an appropriate spine or femur segment in a cadaver with subsequent determination of the weight of the scanned piece of bone after defatting and ashing. Scanning excised pieces of real bone in water with subsequent defatting and ashing is a less exact procedure for determining measurement accuracy. Another acceptable approach to monitor measurement accuracy uses bone ash or hydroxyapatite in anthropomorphic phantoms with known bone mass and with a known projected bone area.(37) Dual-photon absorptiometry can achieve an accuracy error of about 3 percent on phantoms and bone specimens; however, accuracy errors of 3-10 percent are more common clinically.(54,79)

The precision error of DPA measurements is determined by repeated measurements on phantoms and control patients. Routine clinical scans of the spine and femur have precision errors of 2-5 percent. Imprecision largely results from technical factors (as with all radiologic methods), establishment of suitable soft-tissue baselines, and the low and constantly decreasing intensity of the photon source.(80,81) Higher precision measurements (2-3 percent CV) are achieved with careful attention to baselines, bone edges, and quality assurance.

More detailed descriptions of DPA are found in the 1986 OHTA DPA assessment report by Erlichman(3) and in recent reviews by Wahner,(64) Mazess,(70) Lang et al,(72) and Tothill.(75)

Dual-energy x-ray absorptiometry

Dual-energy x-ray absorptiometry is a modification of DPA, using an x-ray instead of a radionuclide source to measure the bone density.(37,82) The advantages of DXA over SPA and DPA, both of which it is rapidly replacing, are scanning speed, low radiation dose, and more precise measurements that make changes in bone density over time easier to assess.(83) Other terms used to describe the dual-energy x-ray technology are quantitative digital radiography, dual-energy radiographic absorptiometry, dual-energy radiography, and dual x-ray absorptiometry. Dual-energy x-ray absorptiometry systems have one x-ray source that produces photons of two distinct energies, a photon detector, and an interface with a computer system for imaging the scanned areas. Table 5 summarizes DXA characteristics.

Table 5. Dual-energy x-ray absorptiometry characteristicsa.

Table

Table 5. Dual-energy x-ray absorptiometry characteristicsa.

Dual-energy x-ray absorptiometry systems have greater photon output (higher photon flux) than radionuclide sources, improved detector configuration, and automated analysis procedures. These developments provide higher spatial resolution, improved precision, shorter scanning times (10 minutes for the lumbar spine and proximal femur and 20 minutes for a total body scan), and reduced radiation dose compared with QCT and DPA.(63,84-86) High-resolution imaging facilitates reproducible bone edge detection, improves visualization of the area measured, maximizes the number of bones measurable, and allows artifacts to be recognized and eliminated from the analysis.(66,82) These improvements become particularly important for analyzing spinal bone density in osteoporotics.(72,87) Increased scan speed reduces errors resulting from patient motion and is also more convenient for patients with back pain.

Like DPA, DXA measurements reflect the total integrated (cortical and trabecular) mineral and any extraosseous mineral in the path of the beam. These techniques determine the bone density from a conventional anterior-posterior image (AP projection). The sites most commonly measured are the lumbar spine, generally L2-L4 or L1-L4. Other sites include the hip (the femoral neck, the intertrochanteric region, and Ward's triangle) and forearm.(72,88)

Dual-energy x-ray absorptiometry scans of the lumbar spine in the lateral projection were recently developed.(66,89) This may minimize the effect of the posterior arch (cortical bone) on measurements as well as aortic calcification and posterior osteoarthritis, conditions common in the elderly that can falsely indicate elevated bone density.(76) This modification makes possible a more sensitive, direct approximation of trabecular bone.(66) The clinical value of this scanning technique is currently being evaluated.(48,90)

The accuracy error of DXA measurements is determined from a calibration of the technique with ashed bone (excised human vertebrae) or equivalent hydroxyapatite (phantom) in the projected area.(37,84,91) Results are expressed relative to the projected area of bone to give an area-specific bone density in g/cm2.

Although reviews of recent studies report DXA accuracy error from 3-6 percent, other data indicate that DXA accuracy error on ashed bone specimens is about 9 percent.(91) According to Kelly et al,(82) systematic errors in DXA measurements at the spine can alter the apparent normal range for bone density in the population. They found that the mean value of populations measured by various DXA instruments may differ by as much as 20 percent.

The precision error of DXA measurements is determined by repeated measurements on phantoms and control patients. Routine clinical scans of the spine and femur have a precision error of .5-3 percent.(76,85,87) These high-precision measurements are largely the result of increased x-ray flux and improved spatial resolution. Long-term precision depends on technician skill for selecting the correct sequence of vertebrae, correct angulation of the leg (femur measurement), and correct bone area. It is essential that the same area be compared each time or additional errors can result.

More detailed descriptions of DXA are available in reports by Wahner et al,(37) Wahner,(48) Kelly et al,(82) and Kellie.(84)

Quantitative computed tomography

Quantitative CT is the application of conventional CT scanners and commercially available software packages to the quantitative measurement of bone density in the spine. Dedicated scanners are necessary to obtain satisfactory measurements of bone density. An advantage of QCT, which measures bone in three-dimensional sections (volume), is its ability to separate cortical from trabecular bone with great anatomic detail. Quantitative CT precision has improved (2-6 percent), and both scanning time (15-20 minutes) and radiation dose (about equal to a chest x-ray, but 200-500 times the DXA dose) have been reduced as a result of new calibration standards, software, and improved scanner design.(83)

Single-energy QCT can be performed with a 100-300 mrem exposure to the upper abdomen, but some scanners may deliver as much as 500-1,000 mrem.(72,89,92,93) The radiation dose is usually substantially higher in clinical settings than in research centers performing the same studies.(76) A summary of QCT characteristics is presented in Table 6. More detailed descriptions are available in recent reviews by Cann,(94) Lang et al,(72) Mazess,(76) and Genant et al.(95)

Table 6. Quantitative computed tomography characteristicsa.

Table

Table 6. Quantitative computed tomography characteristicsa.

Different localization and scanning procedures are used to obtain axial sections at the center of the vertebral body. In principle, total, cortical, or trabecular bone density can be measured centrally or peripherally. In practice, however, the method has been developed to measure the central trabecular portion (the spongiosa) of two to four adjacent lumbar vertebral bodies.(66,72) These representative volumes of trabecular bone are quantified and averaged, and the results are expressed as mineral equivalents in g/cm3. This area covers approximately 35 percent of vertebral trabecular bone and represents a volume of about 3 cm3 of purely trabecular bone in each of the lumbar vertebrae.

With QCT, the change in vertebral (trabecular) bone during the immediate postmenopausal period was reported as 5-7 percent per year, which is about 2-3 times that observed by integral DPA measurements and 3-5 times that seen in the cortical radial sites. Recommendations for monitoring postmenopausal bone loss at the spine with QCT are based on these observations of higher estimates of bone loss. However, overestimation of menopausal spinal bone loss due to variable marrow fat, low precision, and higher radiation exposure have limited this use.(73,75,95)

Although QCT can assess the purely trabecular portion of the spine and may hypothetically provide a more accurate assessment of fracture risk, there is no evidence that this potential benefit outweighs the problems and limitations of the method. Moreover, the contribution of the cortical compartment to crush fracture is being evaluated, and the concept that only the trabecular bone content is important is being challenged.(96,97) No prospective clinical trials with QCT have been conducted to determine its utility for assessing the risk of spinal fractures.

Quantitative CT can be performed with most existing CT units. However, to adapt an existing CT scanner for quantitative measurements of bone density requires software and mineral reference standards (phantoms) with sophisticated calibration and positioning techniques.(78,98) Careful calibration and quality assurance programs are mandatory, especially when the instrument is used both for routine imaging as well as the quantitation of the bone density.(5) However, dedicated scanners are recommended for measurements of bone density. Because CT x-ray output is variable, calibration standards (solutions of varying concentrations of potassium phosphate; K2HPO4) should be measured simultaneously with the patient.(77)

Quantitative CT accuracy is also determined with measurements of vertebral specimens correlated with ash weight. The accuracy error of QCT is 1-2 percent for potassium phosphate solutions and 5-15 percent for human vertebral specimens. A variety of technical factors (scattered radiation, beam hardening, position in the beam, slice orientation) contribute to errors in QCT measurements. Quantitative CT exhibits an accuracy error of 6-9 percent in healthy younger individuals, but becomes increasingly inaccurate (10-15 percent) with aging and with bone disease because of the variability of marrow fat within the vertebral bodies.(70)

The precision error of QCT measurements is determined by repeated measurements on cadavers, phantoms, and patient controls. Some concern remains about the reproducibility of QCT spinal bone density measurements. Despite procedures that have enhanced the technique, some bone studies still show QCT reproducibility to be relatively poor (>3 percent precision error).(99) This is usually because of machine drift and repositioning errors.

The precision error of vertebral QCT in research settings providing exact detail to patient positioning and instrument performance is about 1-3 percent and is 2-6 percent in other settings such as hospitals and clinics.(48,72,94) However, the precision of multipurpose hospital scanners is generally not better than 5-10 percent.(83) In research settings with dedicated CT scanners, quality control for bone density measurements is achieved. However, quality assurance in other clinical settings (e.g., hospitals and offices) is frequently lacking.(89,98)

Although most bone mass measurements by QCT use the single-energy scanner, a dual-energy scanner is available that is usually used for research purposes.(100) Although the dual-energy scanner can correct for changes in marrow fat and increase the accuracy of the measurement, it does so at a cost in complexity, precision, and higher radiation exposures.(89,92)

Quantitative CT techniques have been applied on a limited basis to the measurement of trabecular bone at the femoral neck.(72,92) Because of the complexity of the anatomy, reproducible bone density measurements will probably be difficult. Moreover, both cortical and trabecular bone loss may predispose to femoral neck fractures. Therefore, identification of individuals at risk may thus be improved by considering both types of bone deficit. An integrated measurement of cortical and trabecular bone may more reliably predict femoral strength and fracture risk than an independent assessment of either component.(101)

Ruegsegger et al(102) suggest that cortical bone density and trabecular bone density may complement each other in the diagnosis of bone diseases. They believe that trabecular bone density (radius) is highly sensitive to perimenopausal bone loss or iatrogenic effects of drugs such as corticosteroids. However, the disadvantage of trabecular bone density is the broad range of normal values and its considerable age dependency. In comparison, cortical bone density is limited to a very narrow range and does not show a pronounced age dependency in healthy subjects. An individual deviation of 5 percent from the mean is sufficient to be significant.

A specially constructed CT instrument for the separate determination of trabecular and compact bone density in the appendicular skeleton is available.(77,91,101,102) Although much attention has been given to QCT measurements of lumbar vertebral bodies, a number of factors, including poor precision and accuracy and higher levels of radiation exposure, make this location less than ideal for bone density measurements. In comparison with QCT of the spine, measurements at the radius take less time, have improved precision and accuracy, and expose the patient to less radiation.(103)

Radiographic absorptiometry

Radiographic absorptiometry is a noninvasive radiologic technique primarily used to measure the small bones of the hand (phalanges). It uses a computer-assisted densitometric measurement of the x-ray image of these bones.(104) Similar techniques are referred to as aluminum equivalency, photodensitometry, and radiographic densitometry.(53,98) Measurements of bone density by RA have been used to provide an index for skeletal status in the assessment of renal osteodystrophy,(105) and to assess bone density in studies of bone response to various treatment regimens for osteoporosis and other metabolic bone diseases.(53,106) A summary of RA characteristics is presented in Table 7. More detailed descriptions are available in the 1987 OHTA RA assessment report by Erlichman(4) and elsewhere.(53,75)

Table 7. Radiographic absorptiometry characteristicsa.

Table

Table 7. Radiographic absorptiometry characteristicsa.

Radiographic absorptiometry involves radiation exposure up to 100 mrem, with negligible bone marrow or gonadal radiation.(68) On average, RA delivers about 40 mrem to the patient.(53) Radiographic absorptiometry bone mass analyses are based on phalangeal scans of pairs of lightly exposed radiographs taken at different kilovoltage and exposure settings. An aluminum alloy reference wedge, which allows the computer to compensate automatically for any between-film differences in exposure, kilovoltage, filtration, film type, or film processing conditions, is included in the image field. A computer-controlled optical densitometer scans the x-ray image with a light beam. The density of the film image over the bone is compared with that over the soft tissue, and the resultant absorption is related to normal values of phalangeal bone obtained from age- and sex-matched controls.(4,107)

Although RA can be used to study the metacarpal, radius, and other appendicular bones, it is most often used to measure the phalanges, a mixture of compact and trabecular bone with minimal overlying soft tissue.(75) X-rays of small bones with minimal soft-tissue cover only require multiplication of the optical densitometry measurement by a constant and do not demand immersion of the hand in a layer of tissue-equivalent material (water bath), according to some investigators.(104) Other researchers do not find variations in soft-tissue thickness corrected by a constant multiplier.(53,109,110) This issue remains controversial.

Radiographic absorptiometry was developed in an attempt to circumvent some of the inherent limitations and errors in the use of an x-ray image to measure bone mass. The accuracy error of RA measurements is determined from a calibration of the technique with ashed bones and an aluminum reference wedge. The wedge serves as a standard in which its measured optical density is compared with the optical densities for bone. Certain technical problems inherent in this technique, however, reduce the accuracy of the measurement.(108) The accuracy error for excised bones is 3-5 percent and 5-10 percent for bones with a slight tissue cover.(53,111) As with the other bone densitometry techniques, correcting the measurement for variation in the amount of soft tissue and fat overlying the bone is a problem. The precision error of RA measurements, determined by repeated measurements on phantom hands and patient controls, is between 2 percent and 4 percent.(112-114)

Radiographic absorptiometry has not been used in any prospective studies of women with osteoporosis or renal osteodystrophy, and very little new information is available in the published literature regarding the clinical utility of RA subsequent to the OHTA assessment report in 1987.(4)

Alternative Techniques

Ultrasound

There are those who question whether low bone mass alone is a sufficient explanation for fractures.(10,115,116) Of significance is the discrepancy between bone density and fracture observed in studies in which fluoride caused dramatic increases in the bone density of osteoporotic women without an expected decrease in fractures.(117,118)

Although bone mass correlates well with bone strength, other factors that influence the strength of bone cannot be assessed by bone mass measurements.(119,120) Ultrasound techniques, recently introduced to assess bone mass, can provide information that may be relevant to other aspects of bone quality, such as its geometry, architecture, and biomechanical properties.(121-125) These techniques use either ultrasonic velocity or ultrasonic absorption in bone as an index of bone quality. Preliminary studies(121,123,124) of ultrasound bone assessment are promising and have encouraged interest in the use of ultrasound as a technique to identify women with osteopenia. However, a recent study shows that DXA measurements of the lumbar spine and femoral neck are significantly better than any of the ultrasound findings for determining osteopenia in the hip and spine.(126)

Ultrasound has clinical potential because of its relative low cost and ease of use without the need for ionizing radiation. However, data are too limited to verify the usefulness of ultrasound to assess fracture risk, evaluate bone quality and structure, and identify what characteristics referable to bone quality are being measured.(122)

Biochemical markers of bone turnover

Biochemical markers of bone turnover (bone formation and resorption) may help to determine the rate of bone loss.(24) There is considerable interest in the use of serum and urinary markers of bone metabolism to predict the skeletal status of women at risk of developing osteoporosis. These biochemical markers can reflect the enzymatic activity of osteoblasts or osteoclasts (e.g., alkaline or acid phosphatase activity); can be proteins synthesized by the bone-forming cells (e.g., osteocalcin or procollagen-1 extension peptides); or can be bone matrix components released into the circulation during resorption (e.g., hydroxyproline or the pyridinoline crosslinks).(35)

According to Arnaud,(127) the utility of some bone markers may be limited by factors that make them both insensitive and nonspecific. Hansen et al,(128) however, predicted future bone mass using SPA measurements of peak bone mass and an estimated rate of bone mass loss based on biochemical measurements. They found that the estimated bone loss was almost identical with the actual loss of bone mass measured 12 years later.

Recently, immunoassays have been developed to quantify urinary excretion of pyridinoline and deoxypyridinoline crosslinks. These were shown to measure the degree of collagen degradation and bone resorption. The potential clinical utility of crosslinks measurement will be in the detection of increased bone turnover in the perimenopause, so that osteoporosis prophylaxis can be instituted before appreciable menopausal bone loss occurs.(127) Alone or in combination with bone absorptiometry, bone markers may aid in the identification of patients at high risk for fracture.(129-131)

Part II. Clinical Report

Introduction

Primary hyperparathyroidism (PHPT) is a generalized disorder of calcium, phosphate, and bone metabolism due to the excessive secretion of parathyroid hormone (PTH) from the parathyroid gland(s).(132,133) Chronic exposure to PTH by bones and kidneys causes hypercalcemia, the hallmark of PHPT.(134) Primary hyperparathyroidism is usually caused by hyperfunction of a single (adenoma) or multiple (hyperplasia) parathyroid glands.(134,135) Approximately 100,000 new cases of hyperparathy-roidism are diagnosed each year in the United States.(136) The disease occurs in women more than twice as often as men, and the frequency increases with age. After age 50, the incidence is about 1 per 1,000 males and 2 to 3 per 1,000 females a year.(135)

Parathyroid hormone, along with vitamin D and calcitonin, helps to regulate ionized calcium in the extracellular fluid of the body.(135) Parathyroid hormone synthesis and release are controlled principally by the serum calcium level, and in turn PTH maintains the serum calcium level by promoting calcium entry into the blood at the bone, kidney, and gut. Excess PTH enhances the release of calcium and phosphorus from the bones (bone loss). This creates a higher-than-normal level of serum calcium, increased urinary calcium, and a propensity for renal stones.

Primary hyperparathyroidism is usually diagnosed on the basis of persistent hypercalcemia and an elevated serum PTH level. However, there may be great variation in the clinical presentation of PHPT.(134) When the disorder was first recognized, many patients presented with renal stones or bone disease (osteitis fibrosa cystica).(133) Gastrointestinal signs and symptoms (abdominal pain, constipation, ulcer) were also frequently present. More recently, PHPT has been observed to result in myopathy, weakness, confusion, and fatigue.(135) The changing spectrum of presenting signs and symptoms over time is likely due to the fact that at present most new cases are discovered incidental to an elevated serum calcium detected on routine blood chemistry testing. Half or more of these newly diagnosed cases are asymptomatic, and many others have mild or subtle symptoms.(132) The term asymptomatic primary hyperparathyroidism (APHPT) has been applied to patients with elevated serum calcium levels that remain below 11 mg%, unsuppressible elevated PTH, no bone or stone disease, or renal impairment and no symptoms attributable to PHPT.(135-137) Unfortunately, the term has been used imprecisely, with some authors variably including or excluding patients who have mild or vague symptoms. This report uses the term mild PHPT to include both truly asymptomatic patients as well as those with minimal or mild symptoms.

Background

Before routine screening of serum calcium was initiated in the early 1970s, PHPT was infrequently diagnosed. Screening detection of patients with mild PHPT increased the apparent incidence of the disease fourfold, particularly in patients older than 60 years of age, since about 75 percent of patients with mild PHPT had been undiagnosed prior to screening.(138,139)

All patients with PHPT may be considered potential candidates for parathyroidectomy.(136) However, debate about the proper management of hyperparathyroid patients has intensified with the realization that new cases of PHPT are accompanied by a shift toward clinically milder disease.(140) Some investigators believe, however, that even subclinical abnormalities in skeletal mass and/or renal function are indications for the surgery.(141) Nevertheless, parathyroidectomy is becoming less frequently performed on patients with the mild form of the disease, particularly in the elderly.(142) These patients are usually managed conservatively with monitoring of calcium and PTH levels.

Because mild hyperparathyroidism may be associated with significant PTH-dependent loss of bone, it has been suggested that bone densitometry be used to guide clinical decisions in these patients. At issue is whether the detection of bone loss in patients with mild PHPT effectively alters the medical management. This assessment evaluates the clinical utility of bone densitometry in the management of patients with mild PHPT.

Several important issues must be considered in this evaluation, such as the type and extent of bone loss in these patients, whether they have an increased risk for fracture, and whether parathyroidectomy reduces the risk of fracture.

Review of Available Information

Primary Hyperparathyroidism and Bone Loss

Many studies (Table 8) document cortical bone loss in patients with PHPT (including mild PHPT), with some suggesting that this bone loss may not progress after an initial period.(150) However, PTH-related loss of trabecular bone in these patients remains controversial. Some studies show PTH-related loss of trabecular bone; others suggest that trabecular bone may be preserved in patients with this condition.

Table 8. Bone loss in patients with PHPTa.

Table

Table 8. Bone loss in patients with PHPTa.

Because PHPT is primarily associated with cortical bone loss, single-photon absorptiometry (SPA) of the radius has been used to assess bone loss in most studies (Table 8). Occasionally, quantitative computed tomography (QCT) or dual-photon absorptiometry (DPA) of the spine or hip have been used and, more recently, dual-energy x-ray absorptiometry (DXA). Bone densitometry measurements of the forearm essentially reflect cortical bone at the proximal site. The distal site, while predominantly cortical bone, is considered to have a higher percentage of trabecular bone (approximately 20-25 percent) than other radial sites. Some of the studies cited in Table 8 reported significant bone loss at the mid- or proximal radius;(146,148) others, at the distal and proximal sites(145) or the distal site alone.(149)

In their measurements of the radius, spine, and hip, Silverberg et al(148) showed bone density to be reduced at sites of predominantly cortical bone. The low bone mass density (BMD) measurements they observed in the radius, and supported by bone biopsies, provide evidence for excessive PTH action on cortical bone in patients with mild PHPT. However, cortical bone loss may not progress after an initial period (as yet undetermined). Rao et al(150) reported results of an average 4-year followup of 80 patients with APHPT, who were considered not to be surgical candidates (e.g., forearm bone density not more than 2.5 SD below the mean), and found a mean bone loss of 4 percent, which is no more than the expected loss in a normal population. They concluded that, after an initial phase, APHPT can become a benign condition with limited change in bone density and biochemical indices such as PTH and serum calcium.

The researchers suggested that the adverse effect of mild PHPT on appendicular cortical bone is completed before the diagnosis is made. They proposed a biphasic course of mild PHPT, in which cortical bone is lost during an early period of disease progression, followed by a long period of disease stability. Results from the study by Warner et al(144) support the biphasic progression of PHPT. The researchers reported BMD measurements of the radius as below the mean for normal values at diagnosis, with no further decline in BMD (other than that expected for age, i.e., a loss of 1.8 percent per year) observed during the 2-year followup period.

Recently, Silverberg et al(151) demonstrated similar findings in a study that followed 42 patients with mild PHPT, considered not to be surgical candidates as determined by guidelines reported by the NIH Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism (vide infra).(136) These subjects were followed for up to 6 years. An additional 24 patients were also followed without surgery although they met at least one of the criteria for surgery.

None of the 66 patients developed a new fracture that could be attributed to PHPT and annual measurements showed no longitudinal changes in biochemical profile or bone mass density measured at the lumbar spine, femoral neck, and radius by SPA, DPA, and DXA. In addition to confirming the previous work by Rao et al(150) indicating no progression of cortical bone loss, and extending the observation period to up to 6 years, Silverberg et al(151) demonstrated that untreated mild PHPT is not associated with adverse consequences to the trabecular bone over the period of the study. A subset of postmenopausal women (44 patients) also showed no change in biochemical indices or bone density at any of the three sites. None of the women included in this study was taking estrogens. These results support the position that conservative management of patients with mild PHPT does not lead to progression of disease and bone density is maintained over 6 years of observation at sites reflecting both cortical and trabecular bone.(151)

Controversy continues as to whether there is PTH-related trabecular bone (spine, distal radius) loss prior to diagnosis. Single-photon absorptiometry studies comparing bone density values at the mid-radius with those at the distal radius found a greater loss of bone at the distal site, with its higher percentage of trabecular bone.(145,149,152) With the use of a dedicated QCT system that can differentially measure both cortical and trabecular bone in the appendicular skeleton, Hesp et al(147) also found a greater loss in bone density in the distal radius than in the mid-shaft. They attributed this to the loss of trabecular as well as cortical bone. Similarly, Seeman et al(148) with dual photon absorptiometry and Richardson et al(153) with QCT, observed decreases in BMD at the lumbar vertebrae, a site of predominantly trabecular bone.

On the other hand, a number of studies(148,154) showed BMD measurements of the lumbar spine to be within the normal range. A recent review by Parisien et al(155) indicates a general agreement based on bone biopsies that trabecular bone is preserved in PHPT. Other data not only document greater cancellous bone volume and trabecular number in PHPT patients, but preserved trabecular connectivity as well.(155)

Redistribution of calcium from sites of the appendicular skeleton, where bone is primarily cortical, to sites of the axial skeleton, where bone is primarily trabecular, is consistent with the physiologic actions of PTH.(156) Wilson et al(157) and Silverberg et al(148) proposed that mild PHPT might exert a protective effect against trabecular bone loss and vertebral fracture. Also, some evidence suggests that the dual actions of PTH on the skeleton may depend on its serum concentration. High concentrations are catabolic, particularly on cortical bone. Marginally elevated concentrations, as occurs in APHPT, are anabolic, particularly on trabecular bone.(158,159) For example, findings by Parisien et al(137) indicate that the overall bone balance may be maintained in APHPT. Finding total bone density normal, in spite of a significant loss of cortical bone, suggests that this loss is compensated for by the increase in trabecular bone volume.

Primary Hyperparathyroidism and Fractures

Following a 1989 review of seven published studies from 1981-1985 (totaling 344 patients) on the natural course of untreated APHPT, Lafferty and Hubay(154) concluded that there was no convincing evidence that mild PHPT resulted in progressive osteoporosis. They also pointed out, based on additional literature, that the issue of whether untreated APHPT leads to osteoporosis and multiple fractures of the spine and elsewhere remains unresolved. In a more recent review, Davies(160) pointed out that a bone mass deficit in these patients is inevitable. This is because PTH accelerates bone turnover and greatly increases the formation of new bone that is less mineralized than older bone. Davies found many studies demonstrating reduced bone mass in patients with PHPT, but no "definitive publication" that showed an increased risk of fracture in patients with mild PHPT. Davies proposed studies to assess the risk of fracture in the appendicular skeleton of patients conservatively managed with mild PHPT.

It is not clear from these reviews that bone loss necessarily leads to increased risk of fracture in patients with mild PHPT and, if so, at which sites. Table 9 summarizes some studies that have evaluated the risk of fractures in patients with mild PHPT. Although some studies link PHPT (including mild PHPT) with increased vertebral crush fractures, others do not. While some evidence suggests that enhanced cortical bone loss may contribute to an increased rate of forearm fractures, few studies have investigated the impact of cortical bone loss on hip fractures.

Table 9. Fracture risk in patients with PHPTa.

Table

Table 9. Fracture risk in patients with PHPTa.

Some studies have found higher rates of vertebral compression fractures among patients with PHPT compared with age- and sex-matched control groups. Peacock et al(161) observed a higher prevalence of wrist, hip, and spine fracture in 174 women with PHPT than that predicted from a normal same-aged population. Both cortical and trabecular bone were reduced in these women, with the age-corrected cortical deficit more pronounced in elderly patients. Vertebral fracture was diagnosed when at least four wedged or two crushed vertebrae were present.

The findings of Kochersberger et al(163) also indicated an association between PHPT (including mild PHPT) and vertebral fractures. They found a 1.5-fold greater prevalence of vertebral fractures among 206 patients who underwent parathyroidectomies compared with an age-matched group of patients who underwent cholecystectomy. This control group was chosen because of similar demographic characteristics, lack of bone disease, and readily available preoperative lateral chest x-rays. Within each age group, a higher percentage of patients with PHPT suffered fractures. The APHPT patients had fractures nearly as often (17 percent) as did those with PHPT-related symptoms (23 percent). Neither elevated alkaline phosphatase nor serum calcium levels were associated with fracture rate.

In contrast to these studies, Posen et al(162) found no significant difference in the vertebral fracture rate 8 years postoperatively in a retrospective study of 265 patients with successful parathyroidectomy, unsuccessful parathyroidectomy (continued hyper-calcemia), and no surgery. Aware of a selection bias due to the nonrandomization of patients, the authors nevertheless concluded that the long-term survival and lack of deleterious effects on kidney and bone were similar for both surgically treated and nontreated patients. Wilson et al(157) also concluded that the risk for vertebral fractures was not increased in patients with APHPT. They found in a prospective study over a 10-year period that the prevalence of vertebral fractures in 174 patients with APHPT was not significantly different from that previously observed in a historical control group of 200 healthy white women. The researchers defined both wedge and compression fractures as a reduction in anterior height of more than 20 percent compared with an adjacent vertebra.

Wilson et al(157) and Larsson et al(164) investigated the effect of PTH-related bone loss on wrist fractures. The study by Wilson et al(157) (cited above) found forearm BMD to be decreased 7 percent; 10 cases of wrist fractures occurred in 8 of 174 patients during a 10-year observation period, and no patient had any history of other fractures. Larsson et al(164) observed a 3.5-fold increase in the frequency of distal radius fractures in a group of women with mild hypercalcemia. They recorded 12 distal forearm fractures in 39 women (31 percent), some of whom had no apparent symptoms and had been diagnosed 18 years earlier with mild hypercalcemia (presumably caused by PHPT). In comparison, 3 of the 34 (9 percent) normocalcemic age-matched controls reported distal radius fractures (P < .05). The researchers also found that women <70 years with hypercalcemeia had lower bone density; among the older women (>70 years) there was no difference. Whether PTH-related loss of cortical bone in patients with mild PHPT is associated with an increased risk for forearm, hip, or other osteoporotic fractures remains to be determined.

One explanation for different reports of fracture incidence may be found in the investigation of Mori et al,(165) where the relationship between renal function, vitamin D status, and fracture risk was studied in a small population of postmenopausal hyperparathyroid patients. It was found that both serum 1,25-dihydroxy-vitamin D levels and creatinine clearance values in the patients with fractures were significantly lower than those without fractures. According to the authors, these results suggest that adequate or high 1,25-dihydroxy-vitamin D levels may protect the bone against the resorptive effects of PTH, and that low levels would increase the risk for fracture.

Recently, Melton et al(140) reported PHPT patients (including those with mild hypercalcemia) were more likely than control subjects (matched by age and gender) to have a history of fractures prior to diagnosis (30 percent vs. 18 percent, P = .055). Although over the entire prediagnosis medical history (median, 30 years) almost twice as many PHPT patients had one or more fractures, this difference did not reach statistical significance. Moreover, when only osteoporotic fractures were considered, 10 percent of the patients and 7 percent of the control subjects 35 years of age and older had experienced a fracture, a difference that was not statistically significant. Additionally, from the time of diagnosis both groups had similar rates of fracture during a followup of 12 years (36 percent vs. 31 percent, P = .61). The only factor significantly related to fracture risk was age; serum calcium levels, surgical intervention, or comorbid conditions (e.g., hypertension, renal failure, peptic ulcer) were unrelated to excess fractures. However, whether the bone loss associated with mild PHPT increases the risk of forearm, spine, or hip fractures in specific sub-populations of PHPT patients remains to be determined in much larger studies.

The available information regarding PTH-dependent bone loss and fracture risk indicates that the literature is highly variable and at times contradictory. Although there is evidence in the literature for PTH-dependent osteopenia, the studies cited in Table 9 are equivocal regarding the risk of fracture in patients with PHPT. Some studies indicate no increase in fractures in patients with PHPT,(140,157,162) while others do.(161,163,164) The risk of fracture (past vs. future) in relation to the period of PHPT diagnosis needs further elucidation.

The reason for different findings from various studies may reflect differences in patient selection criteria and definitions and methods of fracture measurement. Also, it has been observed that cortical bone loss was markedly less in U.S. studies.(146) This difference may be due to nutritional status of patients, or the inclusion of more patients with mild hypercalcemia in U.S. studies. This may have resulted from the population's increased intake of vitamin D, which reduces synthesis and secretion of PTH.(156)

Interpretation of results can also be complicated by the possible coexistence of established osteoporosis in the patients studied. Small study populations make it difficult to evaluate the risk of fracture at specific skeletal sites and to control for a rising background frequency of osteoporosis with advancing age. Also, these studies lacked a suitable followup period of time to allow for comparison of bone loss and fracture rates in controls and patients surgically treated or medically monitored.

Primary Hyperparathyroidism and Parathyroidectomy

About 10,000 partial parathyroidectomies are performed annually.(140) Based on the available literature, there are no indices that can predict who among asymptomatic patients will subsequently develop complications of PHPT and require surgery.(166) Successful parathyroid surgery can lead to a reversal of the high turnover state of bone in patients with PHPT.(133) Parathyroidectomy is a highly successful operation, especially when performed by experienced surgeons.(167,168) The success rate of the surgery (normocalcemia) in experienced hands ranged between 85 and 95 percent(142,167,169,170) and, more recently, 95 percent to 99 percent.(168,171) This rate depends also on whether patients have single-gland or multiple-gland disease.(38) Operative mortality is usually low (0-.9 percent).(153,168,170,172)

Operative morbidity can be 8 percent or less when performed in specialized centers by experienced surgeons;(168,171,172) however, it has also been reported to range from 8 percent to almost 20 percent, depending on criteria, surgical technique, and patient mix of single- and multi-glandular disease.(154,167,169,172) Patients with secondary explorations carry a higher morbidity; for example, the total morbidity in one series of 68 patients (including four with previous neck surgery) was 19.2 percent but was 16 percent for the 64 patients without previous neck surgery.(154)

Lafferty and Hubay reviewed and studied the complications of parathyroidectomy (primarily for first explorations) and reported that the combined surgical failure rate, including negative results of neck explorations, persistent hyperparathyroidism, and recurrent hyperparathyroidism ranged from 8-13 percent.(154) According to van Heerden and Grant,(168) the current biochemical diagnosis of PHPT is highly accurate, and cervical exploration is seldom performed for an incorrect diagnosis (negative exploration). Wells(169) reported that approximately 5-9 percent of patients subjected to parathyroidectomy have either persistent or recurrent hyperparathyroidism postoperatively.

The incidence of persistent and recurrent hypercalcemia with that of hypoparathyroidism is inversely related. The incidence of permanent hypoparathyroidism in patients undergoing parathyroidectomy ranges between 1 and 9 percent, depending on the operative strategy used to obtain biopsy specimens.(154,169,172) However, recent reports indicate that the incidence of permanent hypoparathy-roidism following initial surgery may be closer to 1 percent.(168,171) According to Heath,(167) recurrent laryngeal nerve palsy is rare following parathyroidectomy and was not observed in over 200 cases. No permanent recurrent laryngeal nerve injuries were observed by Salti et al(171) in 288 initial parathyroidectomies. However, Lafferty and Hubay(154) reported an incidence of transient vocal cord paralysis and persistent vocal cord paresis of about 3 to 4 percent.

Parathyroidectomy reverses or stops the progression of bone loss in patients with PHPT. The studies in Table 10 that measured bone mass at the radius demonstrated that patients with PHPT have variable increases in bone mass following parathyroidectomy. These increases do not usually continue for more than 1 or 2 years after surgery, with the largest increase occurring in the first year.(146,170)

Table 10. Changes in bone mass following surgery for PHPTa.

Table

Table 10. Changes in bone mass following surgery for PHPTa.

Silverberg et al,(174) in a recent study, observed the effects of parathyroidectomy on BMD at cortical and trabecular bone sites in 34 patients for up to 4 years following surgery; however, since the patients entered the study in different years, 20 were available for analysis after 3 years and only 13 after 4 years. They observed cortical bone density at the radius significantly higher than baseline in 20 patients followed for 3 years after parathyroidectomy. Moreover, in their subgroup of patients who showed the lowest bone density at the radius (n = 9), they observed a more dramatic increase in bone density after parathyroidectomy. In this subgroup, by 3 years, the increase in bone density averaged about 12 percent compared to the group increase that averaged about 4 percent. A wide range of recovery in bone mass that correlates to the extent of the bone loss found before surgery has also been reported by Martin et al.(145)

Earlier work studied cortical bone sites because PHPT was known to have a preferential effect on cortical bone with a relative sparing of trabecular bone. Until this study by Silverberg et al,(174) there were virtually no data showing postoperative effects of parathyroidectomy at trabecular bone sites. At the lumbar spine and femoral neck, they demonstrated BMD had increased by almost 13 percent at 4 years. The significant increases in BMD, at sites of trabecular bone and at cortical sites in patients with markedly reduced BMD following parathyroidectomy, could impact surgical decisions if demonstrated in a larger population over a longer period of time.

Even though patients are cured of hyperparathyroidism, their bone reparation may be incomplete with bone mass density remaining below normal. With an average increase in bone mass of about 8 percent at 20 months after surgery, bone mass was still markedly decreased in the majority of the patients studied by Mautalen et al.(146) Alhava et al(173) found that the bone loss present at the time of surgery reversed postoperatively until, at 4 years, the quantity in patients almost reached those in control subjects. However, after 5 years the bone loss again increased.

Melton et al(140) studied age-related fractures in 90 PHPT patients (including those with mild hypercalcemia) and matched controls. From the time of diagnosis, both groups had similar rates of fracture during a followup of 12 years (36 percent vs. 31 percent). Moreover, there was a lower but not significant reduction in fractures relative to control subjects, in the patients who underwent parathyroidectomy compared with the 53 percent of patients not operated on.

There is some evidence that untreated hyperparathyroidism, even within the mild to moderate range, carries an increased risk of death, particularly from cardiovascular diseases. Whether this risk is reduced by successful parathyroid surgery remains controversial.(175,176) There are no randomized clinical trials comparing surgical treatment with medical monitoring of patients with PHPT, including patients that are asymptomatic or have mild symptoms. According to Peacock,(158) because of the difficulty of finding a minimally enlarged gland at parathyroidectomy and the stable and asymptomatic nature of mild PHPT, there has been a trend to follow APHPT patients medically instead of treating them surgically.(158)

Discussion

Because the possibility exists for excessive PTH-dependent loss of bone associated with an increase in fracture incidence several decades after diagnosis,(158) some clinicians recommend surgery whenever the serum calcium is consistently equal to or higher than 11.0 mg/dL.(153,166) This practice does not appear to be evidence based, because there is no precise relationship between BMD and hypercalcemia in PHPT.(146,177)

Although surgery is the treatment of choice for patients with symptomatic PHPT, for mild PHPT it is not considered routine and may be deferred until symptoms appear, particularly in older patients.(154) Based on the available literature, no indices can predict who among asymptomatic patients will subsequently develop skeletal or other complications of PHPT that require surgery.(145,156) If hypercalcemia is not severe (e.g., <11.5 or 12.0 mg/dL), and if osteopenia, other bone disease, or renal complications are not present, monitoring alone is advised.(132)

Monitoring of patients with mild PHPT involves the measurement of biochemical indices to identify skeletal, renal, or other complications of the disease. The question arises whether bone mass measurements are needed to complement these other measurements and aid in decisions regarding clinical management.

An NIH Consensus Development Conference (October 29-31, 1990) addressed the diagnosis and management of APHPT.(136) Acknowledging the paucity of available data regarding bone loss in patients with APHPT, the Panel nevertheless included "substantially reduced bone mass" with other indications for operative intervention. The Panel recommended parathyroidectomy in patients meeting any one of the following criteria:(136) 1) serum calcium greater than 2.99 mmol/L (12 mg/dL); 2) marked hypercalciuria (>9.98 mmol/d [>400 mg/24 h]); 3) any overt manifestation of primary hyperparathyroidism (nephrolithiasis, osteitis fibrosa cystica, or classic neuromuscular disease); 4) reduced creatinine clearance in the absence of other cause; 5) bone mass more than 2 SDs below the mean for age-, gender-, and race-matched controls; and 6) age younger than 50 years.

Although the NIH Panel stated that surgical therapy can be recommended "solely" on the basis of an abnormally low value of bone density, it was aware that such a decision was controversial in the management of patients with APHPT.

Moreover, the Panel recommendations were not well supported by the data presented at the conference.(178) For example, conference speakers reported that the degree and site of bone loss and associated fracture risks were uncertain (Peacock),(178) and that decreased bone density in nonoperated PHPT patients did not differ from age- and sex-matched controls (Clifton-Bligh et al).(178) Only slight decreases in bone density were observed in PHPT patients; measurements at the radius, femoral neck, and lumbar spine were 79 percent, 89 percent, and 95 percent, respectively, of expected values (Bilezkian et al).(178) It was reported that adverse effects on appendicular cortical bone were completed before the diagnosis of PHPT had been made, as the reduced bone density was not accelerated during followup (Parfitt et al).(178) Annual evaluation of PHPT rarely revealed progression of bone abnormalities in unoperated patients, even those with severe osteoporosis (Neer et al).(178) The need for large cross-sectional studies of the relationship between PHPT and osteoporosis was emphasized (Peacock).(178)

No speakers at the conference presented evidence that supported routine bone densitometry for the selection or timing of surgical intervention, or for validation of the choice of parathyroidectomy based upon any level of bone density. Neither did any provide data demonstrating a clear benefit of routine densitometry for monitoring the course of PHPT.(178)

Some investigators(144,150) have suggested that PTH-related bone loss may have already begun to subside by the time patients are diagnosed and that recovery of bone mass (usually cortical bone at the radius) following parathyroidectomy may be short-lived, even though the hyperparathyroidism is cured. The literature reviewed in this assessment indicates that the usefulness of this surgery to prevent further bone loss and decrease fracture risk remains debatable. However, the recent report(174) of substantial improvement in bone mass density (trabecular bone) at the lumbar spine and femoral neck for up to 4 years following parathyroidectomy may influence decisions regarding the usefulness of this surgery.

Because low bone mass in postmenopausal women is associated with increased risk of fracture, the Consensus Panel(136) assumed that this relationship is likely to be valid in patients with PHPT. However, a correlation between low bone mass and increased risk for fracture in postmenopausal women and patients with a disease such as APHPT, which has unique actions on bone, remains to be established.(159) Mole et al(143) recommend that a patient's concern about future osteoporotic fracture should seldom be a major factor in making decisions about surgical correction of APHPT.(143) More information is required to better understand the level of PTH activity needed to induce anabolic or catabolic effects on bone and the variability between subjects.

Moreover, the importance of declining bone mass in these patients is debatable. For instance, the available data comparing fracture rates of patients with PHPT (including mild PHPT) with those of controls are inadequate. This is due in part to the nonrandomized nature of the studies and to insufficient sample size and duration of followup.

The Consensus Panel agreed that some cases of APHPT are safely managed by nonsurgical medical monitoring that includes bone mass measurements. The Panel acknowledged that the ideal method for monitoring changes in bone mass in these patients has not been adequately identified. The Panel suggested measuring a cortical bone site (forearm), and the measurement be repeated after an interval that is adequate to confidently assess that bone has actually been lost. This interval would be determined by the precision of the instrument and the rate at which bone is lost. As indicated in part I of this assessment, when bone densitometry precision errors range from 2-3 percent, with an annual patient bone mass loss of 1-2 percent (which is typical of patients with mild PHPT), a minimum interval of 3.5 to 8 years would be needed between bone mass measurements to document true loss of bone mass in these patients.

Medical/Scientific Organizational Responses

The Scientific Advisory Board of the National Osteoporosis Foundation (NOF) has published a position paper regarding the use of bone mass measurements in the management of patients with APHPT.(179) It states that APHPT patients may have decreased bone mass at both axial and appendicular sites, and that decreased bone mass detected in some patients with PHPT is accompanied by an increased frequency of vertebral, distal radius, and hip fractures. The Advisory Board recommends bone mass measurements of the radius by SPA or the spine by DPA, DXA, or QCT for patients with APHPT to diagnose low bone mass to identify candidates for surgical intervention. Patients are considered at greater risk of subsequent fracture when the value of the measurement is greater than 1 SD below values for young normal individuals (age 30-35 years). The Advisory Board recommends a repeat measurement in 2-3 years for initial measurements within 1 SD of young normal individuals.

The French government's National Agency for the Development of Medical Evaluation published an evaluation of bone densitometry in October 1991.(180) The evaluation found little evidence in the literature to support the clinical utility of bone mass measurements in patients with APHPT.

A report by the National Health Technology Advisory Panel to the Australian Institute of Health found conflicting evidence on the effects of APHPT on the skeleton.(181) According to the Advisory Panel, further study of these effects is needed before the routine use of bone density measurements in the management of this condition can be justified.

The American College of Rheumatology supports the appropriate use of bone mass measurements of the spine and hip at 6- to 12-month intervals in patients with APHPT. These techniques provide a diagnosis of low bone mass that identifies those at risk of severe skeletal disease, who may be candidates for surgical intervention.

According to the American College of Physicians, information about bone density may influence the evaluation and treatment of patients with APHPT. The College points out, however, that the role and value of bone densitometry for this specific clinical circumstance has not been studied.

Public Health Service Consultations

The Center for Health Care Technology considered information provided by various government agencies in this assessment of bone densitometry for management of patients with APHPT. The National Institutes of Health (NIH) supports the published position of the Scientific Advisory Board of the NOF, described previously, regarding the use and benefits of bone mass measurements in the management of patients with APHPT. According to NIH, direct measurement at the bones of interest are highly desirable because 70-90 percent of the attributable fracture risk can be ascribed to loss of bone mineral if bone density measures are made at the risk site.

According to the Food and Drug Administration (FDA), bone mass measurement devices can provide "estimates" of bone density, but they are not approved for use in diagnosing conditions or for indicating therapy.

The Centers for Disease Control and Prevention (CDC) acknowledge that the management of patients with APHPT is controversial. However, since the long-term benefit of surgical treatment on bone density is far from clearly established, and since the complications of surgery can be permanent, it cannot be determined at present whether use of bone densitometry to guide clinical decisions would result in greater benefit or harm to patients with APHPT. Therefore, routine use of bone densitometry in patients with APHPT is not recommended.

Summary and Conclusions

Many studies document bone loss at diagnosis in patients with PHPT (including mild PHPT) that is greater than would be expected in comparable persons without this condition. However, there is no general agreement regarding the severity of bone mass loss in these patients and the rate at which it progresses. A few studies suggest that such accelerated osteoporosis may be self-limited, with patients showing no further decline in BMD after diagnosis.

There is insufficient evidence to conclude that PTH-related bone loss is associated with an increased risk of fracture. The few studies that have evaluated the risk of fracture in these patients are conflicting. Some evidence also suggests that, like bone loss in these patients, fracture risk may change during the course of the disease. One study found that patients with PHPT (including those with mild hypercalcemia) were more likely than matched controls to have a history of fractures prior to diagnosis, but that both groups had similar rates of fractures during followup. Moreover, the studies of fractures suffer from several limitations, such as nonrandomization of patients, different definitions of vertebral fractures, small study populations, and short followup times.

There is also insufficient evidence to determine the effect of parathyroidectomy on the incidence of fractures in patients with mild PHPT, partly because the natural history of this condition is incompletely understood. Although studies demonstrate that patients with PHPT gain bone mass following parathyroidectomy, the bone reparation is incomplete and bone mass density remains below normal, even though the hyperparathyroidism is cured. Currently, decisions to perform parathyroidectomy are based on signs and symptoms of bone disease, metabolically active renal stones, decreased renal function, fatigue and/or depression, and high levels of serum calcium. Although the use of bone mass measurements has been advocated to aid clinical decisions regarding the risks and benefits of surgery, specific bone changes that indicate the need for parathyroidectomy have not been clearly established. There are virtually no prospective data that evaluate decisions to operate based upon bone mass measurements nor randomized clinical trials comparing the outcome of surgically treated patients with those who have not had surgery.

Based on the literature, bone mass measurements cannot predict who among asymptomatic patients will require parathyroidectomy. There is some evidence that nonsurgically treated patients and those who remained hypercalcemic after unsuccessful surgery lost bone at the same percentage rate as normal control subjects, even though their baseline BMD was significantly lower than that of control subjects. Melton et al(140) reported a greater but not significant excess of fractures, relative to control subjects, in PHPT patients who were not operated on compared to the PHPT patients who underwent parathyroidectomy. Surgical morbidity can be 8 percent or less when performed in specialized centers by experienced surgeons. However, in the absence of controlled clinical trials, the long-term risk/benefit ratio of decisions to operate based mainly upon bone mass measurements remains unknown.

Many studies report that by the time the mild form of PHPT is diagnosed, the mean values for radial BMD are significantly reduced, some by as much as 15-30 percent, compared to age-, sex-, and race-adjusted values. Radial bone mass measurements with the SPA technique may be within 3-8 percent of the patient's true bone mass. However, considering the total amount of bone loss (Table 8) due to PTH, SPA measurements at the radius should nevertheless indicate a reduced bone mass at the time of diagnosis.

It is difficult for bone densitometry to measure bone loss in PHPT patients with precision. The ability to measure rates of change in bone mass over time depends on the magnitude of change, the precision of the method, and the number of measurements taken. SPA, DPA, and DXA are suitable for assessing rates of bone loss in the radius, provided that the interval between assessments is sufficiently long. If the densitometer's precision error is high, its clinical utility is limited by the length of time it takes to detect significant bone loss in patients.

The suggested requisite minimum intervals between measurements that are necessary to reliably detect a reduction in bone mass in PHPT patients (assuming that the accuracy of the instrument is invariable) can be determined from Table 2 in part I of this report. Based upon the most favorable conditions, a 1 percent precision error with assumed annual bone mass losses of 3 percent, requires a testing interval of 1 year. However, it is unlikely that yearly densitometry would be clinically indicated, given the fact that a 1 percent precision error is rarely attained and that a 3 percent annual loss in bone mass in these patients would be distinctly uncommon. A 2 percent precision error with an assumed annual bone mass loss of about 2 percent are parameters more representative of the published data cited in this assessment. In this instance, the minimum interval between densitometry measures necessary to document bone mass loss would be about 3.5 years. Recommendations for repeat measurements in shorter intervals are not supported by the available data.

Quality assurance is of particular importance in the field of bone densitometry, because changes in bone mass density due to disease or treatment are relatively small, typically only a few percent annually. Procedural errors, malfunctioning equipment, or erroneous data analysis may cause substantial problems, even if results are in error by only a few percent. Consequently, equipment and operator performance have to be monitored regularly.

Institutions must maintain strict quality control, including calibration and standardization procedures to maintain both precision and accuracy of measurements. Even with instruments calibrated according to manufacturers' instructions, bone density values obtained by DPA and DXA imaging of spine phantoms have differed by as much as 16 percent. Measurements by individual DXA instruments found to be accurate when using their own standard (lumbar spine phantom) differed by up to 8 percent from other DXA instruments using the same standard.

Because measurements are performed on different types of equipment from several manufacturers, cross-calibration measures are of particular importance. Even if similar equipment is used, cross-calibration measurements are required to ensure consistency in the scan review process and machine performance. Moreover, cross-calibration allows for assessment of accuracy and linearity of bone density readings and can minimize discrepancies in bone density measurements among institutions.

Although all manufacturers provide protocols for reference standards and phantom measurements, there is no industrywide agreement for one specific standard that would provide machine-to-machine comparability. Users and/or manufacturers of bone densitometers need to adopt a uniform procedure for calibrating and standardizing instruments and carry out quality control measurements using an accepted "gold standard."

Appendix A. Abbreviations

  • AP = Anterior-posterior
  • APHPT = Asymptomatic primary hyperparathyroidism
  • BMD = Bone-mass density
  • CDC = Centers for Disease Control and Prevention
  • CHCT = Center for Health Care Technology
  • CT = Computed tomography
  • DXA = Dual-energy x-ray absorptiometry
  • DPA = Dual-photon absorptiometry
  • FDA = Food and Drug Administration
  • g/cm = Grams per centimeter
  • g/cm2 = Grams per square centimeter
  • g/cm3 = Grams per cubic centimeter
  • HCFA = Health Care Financing Administration
  • NIH = National Institutes of Health
  • NOF = National Osteoporosis Foundation
  • OHTA = Office of Health Technology Assessment
  • PHPT = Primary hyperparathyroidism
  • PHS = Public Health Service
  • PTH = Parathyroid hormone
  • QCT = Quantitative computed tomography
  • RA = Radiographic absorptiometry
  • SD = Standard deviation
  • SPA = Single-photon absorptiometry
  • SXA = Similar device that uses an x-ray source
  • WHO = World Health Organization

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