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To the Editor:

As previously reported in Arthritis & Rheumatism, measurement of bone mass in patients with ankylosing spondylitis (AS), shows conflicting results (1). The same appears to occur in the evaluation of biochemical markers of bone metabolism in AS (2).

We reasoned that some of these discrepant results observed in the various studies using urinary markers of bone resorption were attributable to the fact that the markers are expressed in relation to the amount of creatinine excreted, and that considerable variation could be expected due to the fact that various degrees of immobilization related to the ankylosis could lead to distinct levels of creatinine in the urine, altering the amount of pyridinoline present. To bypass these limitations, we assessed serum (rather than urine) pyridinoline values, using the novel serum osteoprotegerin (OPG) assay in a select population of patients with AS.

OPG is a naturally occurring cytokine that is a member of the family of tumor necrosis factor receptors and as such plays a critical role in the regulation of bone resorption. It has been shown that OPG acts as an inhibitor of osteoclastogenesis and increases bone density (4, 5).

We studied 25 patients (23 men and 2 women) with AS, selected from among those attending the outpatient rheumatology clinic of the Hospital Central Santa Casa de São Paulo. The mean age of the patients was 37.0 years, and the mean duration of disease was 13 years (range 1–26 years). All patients fulfilled the New York revised criteria for AS (6). Twenty-three patients had both spinal and peripheral involvement (Table 1). The control group included 40 healthy age- and sex-matched individuals with a mean ± SD age of 44 ± 3 years.

Table 1. Clinical characteristics of 25 patients with ankylosing spondylitis*
  • *

    BASFI = Bath Ankylosing Spondylitis Function Index (see ref. 9); BASDAI = Bath Ankylosing Spondylitis Disease Activity Index (see ref. 8).

Age, mean ± SD years38.5 ± 9.0
Disease duration, mean ± SD years13.5 ± 7.6
Male/female, no.23/2
Peripheral arthritis plus spinal involvement, no.23
Spinal involvement only, no.2
BASFI score, mean ± SD (0–10)5.5 ± 1.9
BASDAI score, mean ± SD (0–10)4.7 ± 2.1

We used the CrossLaps (Osteometer, Copenhagen, Denmark) carboxy-pyridinoline serum assay, performed according to the instructions. The intraassay coefficients of variation were 6.0 and 6.2, respectively; these values were obtained internally using a large group of patients (7). Direct quantitative determination of OPG in serum was performed by a standard 96-well enzyme-linked immunosorbent assay format (Immunodiagnostic, Bensheim, Germany). Disease activity was measured according to published criteria (8, 9). Data were usually reported as the mean ± SEM, with correlations by Spearman's coefficient test. P values less than 0.05 were considered statistically significant.

The results observed are shown in Table 2. The serum pyridinoline values of AS patients were significantly reduced compared with those of normal controls, and serum OPG levels were significantly increased in AS patients compared with controls. There was a significant negative correlation between serum pyridinoline and OPG levels (r = 0.78).

Table 2. Biochemical bone markers in patients and controls*
MarkerStudy groupP
Ankylosing spondylitisControl
  1. a

    Values are the mean ± SD.

Serum pyridinoline, pmoles/liter1,255 ± 9832,176 ± 252<0.01
Serum osteoprotegerin, pg/ml138 ± 2562 ± 43<0.01

Our study shows that in patients with AS, serum pyridinoline levels are reduced at the same time that OPG levels are increased. The lower levels observed in patients with AS suggest that osteoclastic activity is reduced in AS, pointing to the possibility that we may be dealing with low bone remodeling in such patients.

This is the first study of its kind to assess OPG levels in patients with AS. Two pitfalls of our investigation are the fact that OPG is synthesized by various skeletal and extraskeletal tissues and cell types and regulation of this synthesis is dependent on a variety of hormones and cytokines, and the fact that circulating OPG levels may only partially reflect the bone/bone marrow microenvironment. However, these pitfalls are present in all studies of bone biology using serum markers. Taking in consideration that OPG may soon be used for the therapy of bone diseases, our results may also have future clinical aplications.

  • 1
    Gratacós J, Collado A, Pons F, Osaba M, Sanmartí R, Roqué M, et al. Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum 1999; 42: 231924.
  • 2
    Bronson WD, Walker SE, Hillman LS, Keisler D, Hoyt T, Allen SH. Bone mineral density and biochemical markers of bone metabolism in ankylosing spondylitis. J Rheumatol 1998; 25: 92935.
  • 3
    Beck-Jensen JE, Kollerup G, Sorensen HA, Pors Nielsen S, Sorensen OH. A single measurement of biochemical markers of bone turnover has limited utility in the individual person. Scand J Clin Lab Invest 1997; 57: 3519.
  • 4
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 30919.
  • 5
    Hofbauer LC, Khosla S, Dunstan CR, Lacey D, Boyle WJ, Riggs BI. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000; 15: 212.
  • 6
    Moll JM, Wright V. New York clinical criteria for ankylosing spondylitis: a statistical evaluation. Ann Rheum Dis 1973; 32: 35463.
  • 7
    Christgau S, Rosenquist C, Alexandersen P, Bjarnason NH, Ravn P, Fledelius C, et al. Clinical evaluation of the Serum CrossLaps One Step ELISA, a new assay measuring the serum concentration of bone-derived degradation products of type I collagen C-telopeptides. Clin Chem 1998; 44: 2290300.
  • 8
    Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994; 21: 228691.
  • 9
    Calin A, Garrett S, Whitelock H, Kennedy LG, O'Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994; 21: 22815.

Ricardo Prado Golmia MD*, Branca Dias Batista Sousa MD*, Morton Aaron Scheinberg MD, PhD, FACP*, * Center for Clinical Immunology and LID Laboratory São Paulo, Brazil.