Patients with monoclonal gammopathy of undetermined significance (MGUS; a precursor to multiple myeloma [MM] and other lymphoproliferative disorders) are known to be at an increased risk of bone fractures. However, the underlying mechanisms of bone disease in these patients are not well understood. In a study published in Blood Advances, Sigrún Thorsteinsdottir, of the Department of Internal Medicine at Landspítali – The National University Hospital of Iceland in Reykjavik, and co-authors examined bone microstructure among older patients diagnosed with MGUS to determine factors contributing to fracture risk. The findings, though, appear to raise more questions than they answer.
While individuals with MGUS had normal bone-mineral density (BMD), their bone volume was increased compared to patients without MGUS. In addition, men with MGUS had an almost 50% increased risk of fractures, compared with other men. “Our findings suggest an effect of MGUS on bone metabolism that does not affect BMD,” the authors wrote of the findings.
In this cohort study, the researchers screened for MGUS in more than 5,000 older Icelandic participants included in the Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-RS), and measured bone metabolism (BMD and bone volume), as well as subsequent fracture risk, over a median of 6.9 years of follow-up (range = 0-11.3 years). BMD and bone geometry were evaluated using quantitative computerized tomography (QCT) in the lumbar spine and the left hip with a four-row detector CT system.
Patients unable to undergo QCT (those with metal implants at the scanned area or who weighed over 330.6 pounds and were unable to lie supine) were excluded from the study. Another 39 patients were excluded from the analysis because of previous lymphoproliferative disease at baseline, missing blood sample, or M-protein concentration above the limit for MGUS.
The analysis included a total of 5,725 patients (2,419 men and 3,306 women):
- 300 had MGUS (159 men and 141 women; median age = 78 years; range = 67-93 years)
- 275 had light-chain MGUS (LC-MGUS; 156 men and 119 women; median age = 79 years; range = 66-97 years)
- 5,150 did not have MGUS (2,104 men and 3,046 women; median age = 76 years; range = 66-98 years)
A total of 5,305 individuals were included in the bone metabolism analysis, including 269 individuals with MGUS (148 men and 121 women) and 243 individuals with LC-MGUS (141 men and 102 women). The researchers found no difference in integral BMD between the groups at the spine (p=0.34), femoral neck (p=0.72), trochanter region (p=0.35), or total hip (p=0.30).
However, people with MGUS had a significant increase in bone volume in the spine (p<0.001) and total hip (p<0.001).
“This increase in bone volume was more pronounced in men with MGUS, who also had a significantly increased risk of fractures,” the authors reported.
During follow-up, 1,334 fractures were recorded: 74 in the MGUS group (34 in men and 40 in women) and 62 in the LC-MGUS group (19 in men and 43 in women). The risk of fracture was not significantly increased in those with MGUS or LC-MGUS, compared with other AGES-RS participants, but was increased for men with MGUS, compared with other men (hazard ratio [HR] = 1.49; 95% CI 1.03-2.08).
The researchers again noted an unexpected finding: Women with and without MGUS had similar risks of bone fracture (HR=1.02; 95% CI 0.74-1.40). “This suggests an effect of MGUS on bone metabolism in men that is not noted in women, possibly as a result of other stronger risk factors in postmenopausal women,” they wrote, explaining that the generally enhanced rate of bone loss in women with osteoporosis “may mask the effect of MGUS on bone metabolism.”
Eighteen patients with MGUS progressed to MM during follow-up, four of whom had a fracture before progression (2 men and 2 women). In addition, patients with MGUS who developed fractures had a decreased BMD at the spine (p<0.001), femoral neck (p=0.005), trochanter (p<0.001), and total hip (p<0.001), compared with others with MGUS, “indicating that processes known from osteoporosis play a role in fractures in this group, just like in the general population,” the researchers noted.
Overall, though, the risk of fractures had no significant association with the risk of progression to MM, compared with patients with MGUS without fractures (HR=0.77; 95% CI 0.24-2.47).
“Our results do not support measuring BMD in [patients with] MGUS to screen for osteopenia/osteoporosis, as our study shows that they do not have a lower BMD than others in the same age group,” the authors concluded. “Studies are needed to determine how patients with MGUS with increased risk of fractures can be identified and how and if they should be treated prophylactically.”
The study is limited by lack of data about the timing of MGUS development. “Assuming that bone disease develops gradually, we might not find a difference in BMD between the groups because of the limited duration of MGUS,” they noted. The authors added that, because the AGES-RS cohort was mostly white and older than typical MGUS patients, these results may not be generalizable to the larger MGUS population.
The authors report no financial conflicts.
Thorsteinsdottir S, Lund SH, Lindqvist EK, et al. Bone disease in monoclonal gammopathy of undetermined significance: results from a screened population-based study. Blood Advances. 2017 December 21.