• monoclonal gammopathy of undetermined significance;
  • osteoporosis;
  • fracture;
  • bone mineral density;
  • bone turnover


  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

The possible relationships between biochemical measurements and both densitometric and radiographic indexes of skeletal fragility were evaluated in 65 postmenopausal women with monoclonal gammopathy of undetermined significance (MGUS). There was a significantly higher prevalence of vertebral fractures in the MGUS group compared with a control population (P ≤ 0·001). The MGUS patients were then grouped according to the presence or absence of at least one mild vertebral fracture. Patients with fractures (Fx, n = 34) were older (62·8 ± 6·1 years), with long-standing disease (8·8 ± 7·1 years) when compared with those without fractures (NFx, n = 31; 59·7 ± 5·0 years, P ≤ 0·05 and 5·8 ± 4·1 years, P ≤ 0·05). The receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio was higher in Fx compared with NFx (0·092 ± 0·018 vs. 0·082 ± 0·020; P ≤ 0·05). Lumbar spine (0·811 ± 0·14 vs. 0·956 ± 0·12 g/cm2), femoral neck (0·660 ± 0·09 vs. 0·747 ± 0·10 g/cm2) and total bone mineral density (BMD) (0·788 ± 0·11 vs. 0·884 ± 0·11 g/cm2) were lower (all P ≤ 0·001) in Fx-MGUS compared with Nfx patients. Receiver operating characteristic curves identified lumbar BMD as the variable that best predicted vertebral fractures (area under the curve 0·817; 95% confidence interval, 0·713–0·921). This study provides an indication for the measurement of BMD in MGUS patients, as a means of predicting vertebral fractures, especially in those that are asymptomatic. Patients with prevalent fractures should undergo pharmacological treatment to prevent further fractures.

It is well known that multiple myeloma patients are characterised by a negative uncoupling between the two processes of bone remodelling, i.e. bone formation and resorption; this is the main pathophysiological mechanism underlying the skeletal complications typical of the disease, primarily osteoporosis and pathological fractures (Kyle et al, 2003). Nevertheless, it is not yet clear if such a perturbation of the skeletal turnover is already detectable in patients suffering from a haematological disease that can precede myeloma, i.e. monoclonal gammopathy of undetermined significance (MGUS). In this context, a mean significant increase of biochemical markers of bone resorption, in comparison with a healthy control group, has been found in some, but not all, studies carried out in MGUS patients (Pecherstorfer et al, 1997; Diamond et al, 2001; Jakob et al, 2002; Hernandez et al, 2004). Moreover, there are discordant data regarding the behaviour of markers of bone formation (Woitge et al, 2001).

Recent characterisation of novel molecules, such as the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and macrophage inflammatory protein-1 alpha (MIP-1α) has provided new insight into the pathophysiology of bone disease in these disorders. For example, the mean peripheral RANKL/OPG concentration ratio has been shown to be significantly higher in patients with multiple myeloma (Terpos et al, 2003) and a similar result has been documented in a relatively small group of patients with MGUS (Politou et al, 2004).

However, the investigations published to date regarding these haematological disorders, and in particular MGUS, have only considered the single factors potentially involved in the bone damage. In addition, these studies often generated inconsistent results because of a number of biases, such as the small number of patients studied, the inclusion in the same study of patients of both sexes and as regards females, the inclusion of patients in a different gonadal status; it is, in fact, well known, for example, that both the sex and the gonadal status are independent factors that can affect bone mass (Duan et al, 2001). Lastly, it is surprising to note that there has never been an investigation carried out to determine whether the biochemical alterations in patients with MGUS could lead to bone loss documented by densitometric measurements and, therefore, to an increased risk of fractures. A recent paper might indirectly suggest this sequence of events as it reported an increased risk of fractures in the axial skeleton of patients with MGUS with respect to the general population (Melton et al, 2004).

We studied a homogeneous group of postmenopausal women with MGUS, to evaluate the possible relationships that exist between biochemical measurements and both densitometric and radiographic indexes of skeletal fragility.

Patients and methods

  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References


We studied 65 postmenopausal women (age, mean ± standard deviation (SD): 61·3 ± 5·8 years; mean time since menopause 10·8 ± 6·7 years) suffering from de novo MGUS diagnosed at the Haematology Institute of the University of Rome ‘La Sapienza’ (Italy), between 1980 and 2001. The diagnosis of MGUS was made according to standard criteria (briefly, serum protein electrophoresis showing a monoclonal protein concentration less than 30 g/l; plasma cell content less than 10% in the bone marrow examination, absence of renal failure, anaemia, hypercalcaemia and lytic bone lesions when the X-ray skeletal examination was performed). In each patient immunofixation was performed to determine the type of the monoclonal protein. The final group investigated included 59 patients with IgG, five patients with IgA and one patient with IgM monoclonal serum protein. Patients were contacted by telephone in January 2002 and in the same year, from March to May they came to our Mineral Metabolism Centre of the University of Rome, ‘La Sapienza’. After informed consent was obtained from the participants to be involved in the study, each patient underwent a general medical examination and biochemical routine tests to exclude possible causes of secondary osteoporosis. None of the patients enrolled had ever taken any treatment which could interfere with mineral metabolism (steroids, diuretics, thyroid hormones, anticonvulsant drugs, lithium, etc.). Other exclusion criteria were a previous diagnosis of involutional osteoporosis and treatment with active drugs affecting skeleton turnover (oestrogens and progestins, bisphosphonates, fluorides, calcitonin, calcium and vitamin D supplements). One hundred and thirty healthy postmenopausal women of similar age (60·8 ± 5·3 years) and menopausal status (years since menopause 10·5 ± 6·9) served as a control group for vertebral fracture evaluation; they were chosen (by matching two of them for each MGUS patient) from a population of ambulant postmenopausal women studied during the same period of time (Romagnoli et al, 2004). The study was approved by our local Ethics Committee.

Laboratory methods

Each patient enrolled in the study, underwent a morning fasting blood sample utilising red-stoppered Vacutainers (for the determination of serum protein electrophoresis, creatinine, main parameters of calcium-phosphorus metabolism and markers of skeletal turnover) and one purple-stoppered Vacutainer for haemachrome measurement. Routine blood tests were carried out the same day, the remainder of the blood samples were immediately centrifuged, separated in aliquots and frozen at −80°C until assayed. The assays were completed within 3 months from the time the blood samples were taken. Haematological parameters were determined using the haematology analyser from Bayer (ADVIA 120; Diamond Diagnostics, Holliston, MA, USA). Serum protein electrophoresis and immunofixation were evaluated by the Hydrasys system (Sebia, Italy). Serum levels of total calcium (Ca), phosphorus (P), magnesium (Mg) and creatinine (Cr) were measured by means of a multi-channel analyser (Technicon Autoanalyzer RA 500, Tarrytown, NY, USA). Ionised calcium was measured, immediately after sampling, by use of an ion-specific electrode (Nova 8, ion selective electrode; Nova Biochemical, Walthman, MA, USA), as previously described (Minisola et al, 1993). Creatinine clearance (CrCl) was estimated by the formula (Cockcroft & Gault, 1976), taking into consideration serum creatinine (μmol/l), age (years), body weight (kg) and gender; estimated creatinine clearance = (140 − age) × weight × K/serum creatinine; the constant K being equal to 1·04 for women. Serum levels of calcidiol [25(OH)D] were determined by radio-immunoassay (DiaSorin Inc., Stillwater, MN, USA) as previously described (Hollis et al, 1993), which had intra- and inter-assay coefficients of variation of 8·1 and 10·2% respectively. Circulating parathyroid hormone (PTH) levels were determined by an immunoradiometric assay, which measured serum hormone levels by using two affinity-purified polyclonal antibodies, one specific for the aminoterminal 1–34 portion of the PTH molecule and the second specific for the 39–84 sequence of the hormone (N-tact PTHSP, DiaSorin Inc., Stillwater, MN, USA). Intra- and inter-assay coefficients of variation, in our laboratory, were less than 3·0 and 5·5% (Pepe et al, 2005). Serum levels of C-terminal telopeptide of collagen type I (βCTX) were measured by enzyme-linked immunosorbent assay (ELISA) (Serum CrossLaps ELISA, Nordic Bioscience Diagnostics A/S Herlev, Denmark) (Rosenquist et al, 1998). Intra- and inter-assay coefficients of variation, in our laboratory, were less than 5·1 and 5·4% respectively. Bone isoenzyme of alkaline phosphatase (BALP) was determined with an immunoenzymatic assay (Metra BAP EIA Kit, Quidel Corporation, San Diego, CA, USA) (Gomez et al, 1995); intra- and inter-assay coefficients of variation were less than 5·6 and 7·8% respectively. Serum osteocalcin (BGP) was determined with an immunoradiometric assay (BGP; N-tact Osteo SP, DiaSorin, Stillwater, MN, USA) (Minisola et al, 1999); intra- and inter-assay coefficients of variation were less than 4·5 and 9·5% respectively. Bone sialoprotein (BSP) was determined using a radioimmunoassay (Immunodiagnostik AG, Bensheim, Germany) described elsewhere (Karmatschek et al, 1997). Intra- and inter-assay coefficients of variation were less than 6% and 9% respectively. Serum concentration of OPG and of the soluble receptor activator of nuclear factor kappa B ligand (RANKL) were both measured by ELISA (Biomedica, Vienna, Austria); the ratio of these two parameters was obtained for all patients. Intra- and inter-assay coefficients of variation, in our laboratory, were less than 10 for OPG and 5% and 9% respectively for RANKL. Each patient and control subject underwent standardised lateral radiographs of the thoracic and lumbar spine, centred at T8 and L3, respectively, at a film focus distance of 105 cm. After visual inspection of these radiographs by two independent experienced observers, vertebral deformity was defined when anterior, middle or posterior height loss was more than 20% with respect to the adjacent vertebra, according to Genant's method (Genant et al, 1993). Bone mineral density (BMD) of the lumbar spine (L1–L4) in the anterior–posterior projection and of the hip (femoral neck and total hip) was measured in each patient with dual energy X-ray absorptiometry (Hologic QDR 4500, Hologic Inc., Waltham, MA, USA). The precision error of lumbar spine and total hip measurement was 1·3 and 1·7% respectively.

Statistical analysis

The data are expressed as mean ± SD. Significance between means was assessed using the Student's t-test, a value of P ≤ 0·05 being considered statistically significant. Correlations between BMD and biochemical markers of bone formation and resorption were assessed using linear regression. Frequencies were compared using chi-squared test. Receiver operating characteristic (ROC) curves were designed to identify which of the parameters studied was best suited to predict the patients with fractures. For each ROC curve, specificity and sensitivity were calculated (95% confidence interval, CI), as well as positive predictive value (PPV) and negative predictive value (NPV). The statistical analyses were carried out using the Statistical Package for the Social Sciences software (release 10; SPSS Inc., Chicago, IL, USA).


  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

Eighty-seven per cent of patients contacted by telephone call satisfied our established criteria and/or were willing to participate in the investigation. Table I shows anthropometric, biochemical and densitometric data of the whole sample group. When the patients were investigated, the mean time from initial MGUS diagnosis was 7·4 ± 6·0 years (range 1–22 years).

Table I.   Mean ± SD values of anthropometric, biochemical and densitometric parameters in patients affected by MGUS considered as a whole group and subdivided on the basis of the presence of vertebral osteoporotic fractures.
 Total (n = 65)MGUS Fx (n = 34)MGUS NFx (n = 31)
  1. MC = monoclonal protein concentration. For other abbreviations see Patients and Methods in the text.

  2. *P ≤ 0·05; ***P ≤ 0·001 compared with MGUS Fx.

Age (years)61·3 ± 5·862·8 ± 6·159·7 ± 5·0*
Height (m)1·60 ± 0·051·59 ± 0·041·60 ± 0·06
Weight (kg)70·7 ± 11·869·6 ± 11·872·0 ± 11·9
BMI (kg/m2)27·7 ± 4·627·6 ± 5·027·9 ± 4·2
Years since diagnosis7·4 ± 6·08·8 ± 7·15·8 ± 4·1*
Hb (g/dl)12·9 ± 1·012·9 ± 0·912·9 ± 1·1
Cr (μmol/l)73·4 ± 11·573·4 ± 12·474·2 ± 17·7
CrCl (ml/min 1·73 m2)80·5 ± 18·277·1 ± 17·784·3 ± 18·3
MC(g/l)19 ± 519 ± 520 ± 4
Ca (mmol/l)2·40 ± 0·092·40 ± 0·112·39 ± 0·08
Ca2+ (mmol/l)1·24 ± 0·041·25 ± 0·041·24 ± 0·04
P (mmol/l)1·19 ± 0·181·18 ± 0·141·20 ± 0·22
BALP (U/l)29·3 ± 10·029·7 ± 11·628·9 ± 7·9
25(OH)D (nmol/l)47·3 ± 23·246·2 ± 22·148·5 ± 24·6
PTH (ng/l)34·9 ± 11·135·5 ± 11·334·3 ± 11·1
BGP (μg/l)7·0 ± 2·76·7 ± 2·57·3 ± 3·0
βCTX (ng/ml)0·85 ± 0·360·92 ± 0·330·77 ± 0·38
OPG (pmol/l)3·63 ± 1·183·82 ± 1·273·44 ± 1·06
RANKL (pmol/l)0·34 ± 0·370·34 ± 0·230·33 ± 0·49
RANKL/OPG ratio0·09 ± 0·040·092 ± 0·0180·082 ± 0·020*
BSP (ng/ml)10·8 ± 7·09·1 ± 4·212·5 ± 9·0
BMD L1–L4 (g/cm2)0·880 ± 0·150·811 ± 0·140·956 ± 0·12***
T-score L1–L4−1·52 ± 1·34−2·1 ± 1·3−0·84 ± 1·04***
BMD neck (g/cm2)0·702 ± 0·100·660 ± 0·090·747 ± 0·10***
T-score neck−1·38 ± 0·93−1·75 ± 0·80−0·99 ± 0·90***
BMD total (g/cm2)0·834 ± 0·120·788 ± 0·110·884 ± 0·11***
T-score total−0·89 ± 0·99−1·26 ± 0·91−0·45 ± 0·91***

According to the diagnostic criteria of bone mass measurement of the World Health Organization [normal (T-score ≤ 1·0 SD), osteopenic (T-score between −1·0 SD and −2·5 SD) and osteoporotic (T-score ≤ −2·5 SD) subjects in at least one of the two sites examined), it could be noted that 13 females had normal densitometric values (20% of the sample group), 35 female were osteopenic (53·8%) and 17 were osteoporotic (26·2%).

Table II shows the number and type of fractures found in patients suffering from MGUS and their subdivision based on densitometric classes. X-ray morphometric examination of the spine showed that there were 34 patients with at least one mild vertebral fracture; seven of them had two vertebral fractures and two of them had three vertebral fractures. One osteopenic and two osteoporotic patients had a positive history of Colles fracture. In contrast, there were 31 control subjects in which one mild vertebral fracture was detectable (P ≤ 0·001 vs. patients with MGUS).

Table II.   Number of fractures seen in the sample group (65 women) and their subdivision based on densitometric values.
T- scoreVertebral fracturesColles fracture

The 65 MGUS patients were further subdivided into two groups on the basis of the presence or absence of osteoporotic fractures (Table I). The two groups were significantly different from each other only for a few parameters. In particular, patients with fracture (Fx) were significantly older (P ≤ 0·05) and had long-standing disease (P ≤ 0·05) when compared with non-fractured patients (NFx). Concerning bone remodelling parameters, mean levels of serum osteocalcin were lower and mean levels of serum βCTX were higher in Fx in comparison with NFx, even if these differences did not reach statistical significance. However, mean values of RANKL/OPG ratio in Fx patients were significantly higher with respect to NFx (P ≤ 0·05). BMD values, considered both in absolute and T-score terms, were significantly lower (P ≤ 0·001) at all the sites examined in fractured MGUS patients with respect to those without fractures. An inverse correlation was also observed between serum levels of βCTX and mineral bone density values evaluated both at the lumbar spine site (r = −0·46; P = 0·006) and at the femoral neck site (r = 0·34; P = 0·04) in MGUS patients with fractures.

Finally, ROC curves were designed to define the strongest parameter that was predictive of vertebral fractures in the sample studied. The following variables were taken into consideration: age, years since MGUS diagnosis, monoclonal component concentration, serum levels of βCTX, BALP, BGP, BSP, the RANKL/OPG ratio and the mineral bone density at lumbar spine and femoral sites. Figure 1 indicates that lumbar BMD was the strongest predictor of vertebral fractures, as the area under the curve was equal to 0·817 (95%CI: 0·713–0·921). Therefore, at a lumbar BMD of 0·900 g/cm2, the sensitivity was 76·5% and the specificity was 63·3% considering the prevalence of vertebral fracture in the studied sample group (52%). The corresponding PPV was 70·3% and the NPV was 70·4%. Considering a lumbar BMD value of 0·850 g/cm2, the sensitivity was 67·6% and the specificity was 80·0% with a corresponding PPV of 79·3% and NPV of 68·6%.


Figure 1.  Receiver operating characteristic curves for the relationship between bone mineral densities at three sites and vertebral fractures. LS, lumbar spine; neck, femoral neck; total, total hip.

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  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References

To our knowledge, this is the first study in which the biochemical parameters of bone remodelling, along with densitometric and morphometric indexes, have been simultaneously studied in a homogeneous group of patients affected by MGUS.

The most important finding of our investigation is the elevated prevalence (52%) of morphometric vertebral fractures in postmenopausal women affected by MGUS, with respect to a control population of similar characteristics. This prevalence also appears to be high in relation to international studies carried out with the same definition criteria of vertebral fracture (Genant et al, 1996; Vogt et al, 2000). It is important to note that the presence of a vertebral fracture, even if asymptomatic, increases the risk of new fractures both vertebral and extra-vertebral, independently of BMD value (Pongchaiyakul et al, 2005). Confirming this statement, we detected 26·5% of the patients with more than one vertebral fracture.

In contrast to these observations, there was no history of extra vertebral fractures, except for three Colles fractures reported by three patients. This discrepancy should probably be ascribed to the fact that the axial skeleton contains marrow haematopoietic cells which are able to amplify, through local factors, stimuli leading to increased bone tissue destruction. The absence of bone marrow in the peripheral skeleton justifies, for example, the minor risk of fracture at femoral level, in comparison with the spine, reported in patients with multiple myeloma (Dhodapkar et al, 1998; Melton et al, 2004).

To better understand the mechanisms that underlie the increased fragility of the axial skeleton found in our patients with MGUS, we divided them into two groups according to the presence or absence of vertebral fractures. Three parameters were significantly different between the two groups, i.e. age, duration of disease and the RANKL/OPG ratio. The probability of being affected by MGUS increases with age, as does the risk of skeletal fractures; therefore, our findings could be considered the result of a casual association. However, the high prevalence of vertebral fractures compared with other populations with similar characteristics lead us to consider this hypothesis as unlikely. If we assume that in benign monoclonal gammopathy there could be a basic alteration of the remodelling that favours bone tissue loss, then the duration of the disease represents an important factor conditioning the fracture risk. We did not find any statistically significant differences concerning the mean values of markers of bone remodelling, even though the mean serum values of osteocalcin were reduced and those of carboxy-terminal telopeptide were higher in patients with fractures in comparison with non-fractured patients, thus indicating a negative uncoupling of the balance at the level of the single multicellular basic units. However, it is important to emphasise that the mean RANKL/OPG ratio was significantly higher in patients with fractures. This means that the balance of bone remodelling was unbalanced in favour of bone resorption and suggests a pathogenetic basis for the reduced BMD and the high prevalence of vertebral fractures in these patients. This finding has been further supported by the inverse correlation found between the values of BMD (mainly at the lumbar level, but also at the femoral site) and the serum levels of the collagen type I carboxy-terminal extension peptide (a marker of bone resorption). Regarding this last aspect, it is important to remember that previous studies demonstrated that the RANKL/OPG ratio was higher in patients affected by multiple myeloma, was related to the extension of bone pathology and could be considered as a negative prognostic index of survival (Giuliani et al, 2001; Terpos et al, 2003). Subsequently, this ratio has also been proposed among the indexes of the disease progression from MGUS to MM (Politou et al, 2004).

Apart from the pathogenetic mechanisms involved, from the point of view of clinical practice, the only factor capable of predicting the presence of a vertebral fracture (among all parameters taken into consideration) has proven to be BMD measured at the lumbar level, as demonstrated by the analysis of the ROC curve. In the range of values between 0·900 and 0·850 g/cm2, we have ascertained values for sensitivity and specificity that are suitable for alerting patients to the need to undergo a spine radiograph.

This study provides, for the first time, an indication for the measurement of BMD in patients affected by MGUS, as a means of predicting the presence of vertebral fractures, especially in those that are asymptomatic. Until now, X-ray examination of patients suffering from MGUS has been carried out to exclude the presence of lytic bone lesions, without taking into serious consideration possible morphometric vertebral modifications. It should be noted that the detection of a vertebral fracture is extremely important, because it is forecasts of future fractures, independent of the skeletal factors that determine resistance, and is therefore in need of immediate treatment.

In conclusion, we propose that benign monoclonal gammopathy should be included among the causes of secondary osteoporosis. It is important that patients with this disease should be considered from a morphometeric and densitometric point of view at the first visit and have repeated BMD evaluation during follow-up. In fact, this strategy will allow for the recognition of eventual changes in BMD that could predict vertebral fracture. Finally, patients with prevalent fractures, as well as those with a reduced BMD, should undergo pharmacological treatment to prevent further fractures or to strengthen the skeleton.


  1. Top of page
  2. Summary
  3. Patients and methods
  4. Results
  5. Discussion
  6. References
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