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VOLUME 146 NUMBER 1JULY 2005

THIS MONTH IN J Lab Clin MedIssue Highlights for July 2005

one turnover enzymes: Can their levelserve as markers for the risks associatedith osteopenia or osteoporosis?

In the last five years, several authors have described an important role for Cathepsin K—aapain-cystein protease—in the bone-resorptive function of osteoclasts. Osteoclasts synthesizeathepsin K and secrete it into the extracellular space, where it degrades many bone matrix proteins,

ncluding type I collagen, osteopontin and osteonectin. It seems reasonable to speculate that thisnzyme may be important—either pathogenetically or as an interventional target—in disordersharacterized by imbalance between bone resorption and new bone formation, such as osteoporosis.his idea is supported by the finding that pycnodysostosis, a syndrome characterized by bone

ragility, is associated with mutations in the Cathepsin K gene, as well as by studies in which drugsnhibiting Cathepsin K have inhibited bone resorption in animal models.

It was already known that patients with early-onset osteopenia had high levels of Cathepsin K inhe serum; might that association be tight enough for assay of the enzyme to be useful as a predictorf morbidity due to premature bone loss? That question was explored by Dr. Gerold Holzer andolleagues from the Medizinische Universität Wien, who present their findings beginning on page3 of this month’s issue of the Journal.

Blood samples were obtained from 162 patients with bone loss (101 classified as osteoporotic and8 as osteopenic by DEXA criteria) and were compared with samples obtained from normal controlubjects. Cathepsin K level was measured by an immunoassay, and several other markers of boneurnover were also assessed (alkaline phosphatase [bone fraction], osteocalcin, parathyroid hor-one, C-telopeptide). It was also noted which patients had and which had not suffered fractures in

he absence of explanatory trauma.As expected from earlier results, the patients with bone loss disease had higher levels of Cathepsinthan did normal control subjects. The ranking was also as one might have predicted: The highest

evels were in those with the lowest bone density. Osteoporotic patients had an average serumathepsin K level of 8.8 pmol/L; osteopenic patients had an average value of 6.9 pmol/L, andormal subjects had an average level of 5.4 pmol/L. The Cathepsin K level was also significantlyigher in serum from patients who had suffered non-traumatic fractures than it was in patients whoad not had such complications. Those who had suffered multiple non-traumatic fractures hadigher Cathepsin K levels than did patients who had had only a single fracture (but this difference

Lab Clin Med 2005;146:1–4.

022-2143/$ – see front matter

2005 Mosby, Inc. All rights reserved.

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id not achieve statistical significance in the number of patients studied). Some of the patients beganherapy for osteopenia/osteoporosis (e.g. with bisphosphonates) and follow-up samples becamevailable; these showed a decline in the Cathepsin K level while on therapy. Finally, although somef the other markers correlated with risk of fracture, none did so closely enough to achieve statisticalignificance.

This study was not powered to answer two important questions. First, does the measurementf serum Cathepsin K outperform or significantly supplement the measurement of bone densityn the prediction of fracture risk? Second, is the value in an individual patient stable enough thatne can rely on a single sample for clinical decision-making? Even if the test adds little to theEXA scan when tested on a larger scale, it would require no on-site special equipment and

ould provide cost savings and convenience in comparison to repeated DEXA scans. And in anyvent, the study adds strong support to the idea that Cathepsin K is an important actor inemineralization.

arenteral iron: Allergy and patientiscomfort may not be the only risksorth considering

Iron deficiency is a common cause of anemia, especially in people with unusually high ironequirements: pregnant women, children and adolescents during growth spurts, patients with chroniclood loss. Less commonly, patients may fail to absorb iron normally because of inflammatoryowel disease or surgical changes to the gut—or even because of highly effective suppression ofastric acid production by proton-pump inhibitors. More recently, it has been found that the poorron utilization that characterizes the anemia of chronic disease may respond to the simultaneousdministration of iron and erythropoietin. Each of these clinical situations may create a need forarenteral iron supplementation—either because the medical problem itself involves the gut, orecause the afflicted patient is intolerant of the gastrointestinal irritation caused by oral iron salts.For many years, the iron treatment of choice for such situations has been iron dextran complex.

his may be given as intramuscular injections, or it may be given intravenously. It has the attractiveeature that the iron is released slowly, so a total-body-repletive dose may be given at a single visitithout serious systemic iron toxicity. However, when this is done, there may (rarely) be serious

llergic reactions to the dextran, or there may be (rather more commonly) a syndrome of arthralgiasnd myalgias that can be quite uncomfortable for several days. In the last few years, preparationsave become available in which the iron is complexed with simpler (non-antigenic) sugars; the riskf serious allergy is thus virtually eliminated, and nuisance symptoms are less common. As a minorisadvantage, the iron is not as tightly complexed and the individual iron dose must be limited;ypically, 6-10 doses on non-consecutive days are needed to replete iron stores.

An obvious question arises: although the newer, simpler iron preparations are better toleratedlinically and in the short run, are there differences in the longer-term and/or clinically more subtleafety of the two types of iron preparations? Might there even be a hidden price for protecting theatient from joint pains? This question is the subject of a study by Dr. Toru Sanai and associatesrom the Kyushu University, Fukuoka, Japan and the Kurume University, Kurume, Japan.

As described beginning on page 25, these researchers administered iron intraperitoneally to ratsn either the form of iron dextran or the form of saccharated iron oxide. They then looked forvidence of histologic damage or disordered renal tubular function at intervals up to 28 days.

No histologic evidence of injury was found in any of the animals, so interest centered on tubularunction. The rats receiving the saccharated iron oxide had lower serum calcium, total protein,lbumin and phosphorus levels than did the rats receiving iron dextran. The fractional tubulareabsorption of phosphorus was significantly greater in the group receiving iron dextran than it wasn the group receiving saccharated iron oxide. The authors concluded that saccharated iron oxideaused a defect in tubular resorption of phosphorus, leading to hypophosphatemia.

How big a “deal” is this, anyway? Dr. Rajiv Agarwal of the Indiana University puts these

bservations into a broader context in an editorial on page 5.

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J Lab Clin MedVolume 146, Number 1 In this Issue 3

ssays in translational medicine: The layf the land and the framing ofypotheses—an overview ofbservational research

One often hears a research proposal criticized as being “nothing more than a fishing expedition”;wag once pointed out that a fishing expedition was exactly what was needed if the goal were to

atch fish. In thinking about the ideal of hypothesis-driven research, in which the goal of thexperiment is to support or weaken a specific proposition, it’s easy to forget that those propositionsust come from somewhere. Sometimes, of course, they are born of a previous generation of

ypothesis-driven studies: surprise results or results weakening a previously held belief oftenuggest a revised hypothesis and a new set of tests. But sometimes they arise out of the systematicbservation of a set of conditions, without a pre-formed hypothesis in mind. Depending on theiscipline involved, different terms have been applied to these different types of research—ometimes the labels chosen (e.g. “qualitative” versus “quantitative” research) do as much toonfuse as to clarify. For some discussions, it may be serviceable to compare “hypothesis-enerating” research with “hypothesis-testing” research.In biomedical research, the studies we think of as “observational” or “hypothesis-generating” are

ften surveys of population characteristics, and the first “hypothesis-testing” research they spawnay be more refined and focused surveys of population characteristics. There is also sometimes a

everse side to this “coin”: observations in traditional bench research may suggest a mechanism forpopulation difference, and an observational study comparing populations may be the most direct

est of that mechanism.In the current issue of the Journal, Dr. Russell Leupker of the University of Minnesota provides

n overview of some of the types of experimental design used in observational research, outliningheir strengths and weaknesses. His essay may be found beginning on page 9.

ack to bone density: Where does leptinit in?Leptin is a hormone that is important in the regulation of body mass, and it stimulates boneineralization in some animal models. There are also circumstances in which it may promote cell

roliferation, so a role has been suggested for the protein in tumorigenesis. Although a number oforrelations have been shown, the interrelationships among obesity, leptin levels, bone mineralensity (BMD) and breast cancer are not yet clear. Adding another layer of interest and complexityo the story, there have been studies showing racial or ethnic differences in risks for obesity,steopenia and breast cancer—and it’s not clear if leptin is involved.A study in this month’s issue of the Journal tries to address some of these questions. Dr. K-L.

atherine Jen and several fellow researchers from the Wayne State University obtained bloodpecimens for leptin analysis from breast cancer patients and controls. The ethnic composition wasescribed as 49% white and 51% black women. Bone density was measured in the distal androximal radii of the subjects by DEXA scan; Z-scores were calculated based on ethnicity-specifictandards. Blood leptin levels were determined by radioimmunoassay.

The blood leptin levels were not systematically different between breast cancer patients andancer-free controls. Leptin levels were significantly higher, however, in black women than in whiteomen, and (as expected) they were also significantly higher in overweight women than in womenf normal weight. Some of this difference could be explained by the fact that the women identifieds black in this study weighed more and had higher body mass indexes than did the women identifieds white.

After controlling for body mass index, the leptin level was correlated with bone mineral density

t both sites measured, but that correlation really only held up in the women identified as white.

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J Lab Clin Med4 In this Issue July 2005

At the simplest level, this study suggests that leptin levels may be a useful marker for boneineral density, and might find its way into risk scores for research or clinical use. It also suggests

hat leptin might have a significant role in bone mineralization in people, not just in constrainednimal models. But perhaps the more tantalizing question is: Why a racial difference? Unfortu-ately, we are not told what criteria were used for racial assignment or how those criteria werepplied; we therefore don’t know just who would have been put in which group (a problem in tryingo replicate a study). We also don’t know whether the criteria used for “ethnicity-specific” DEXAtandards are the same criteria the authors used for their group assignments (and whether the baseopulations were similar in genetic heritage)—this can be a problem because the use of suchdjusted standards may falsely assume the equivalence of a biological variable in genetically veryifferent populations who happen to share a similar skin color. So we should probably for theoment view that finding as a “tickler”: a really interesting observation that cries out for a more

igorous examination.The paper by Jen et al may be found on page 18.