In this issue of Blood, Farr et al showed that patients with monoclonal gammopathy of undetermined significance (MGUS) have increased cortical bone porosity and reduced bone strength,1 conditions that can lead to the increased fracture risk, which has been reported in MGUS patients.2
The importance of understanding the mechanisms of bone loss in MGUS is of extreme value as the majority of these patients do not receive any bone targeted therapy, despite their twofold higher tendency to develop fractures, mainly in the axial skeleton, compared with age- and gender-matched controls.2 Furthermore, these mechanisms will allow us to uncover the best imaging technique for the early depiction of bone damage in MGUS patients. Bone densitometry assessed by dual-energy X-ray absorptiometry (DXA) scan is a noninvasive quantitative method for the assessment of fracture risk in osteoporosis. Nevertheless, DXA visualizes bones as a 2-dimensional image and offers almost no information for the 2 factors that determine bone strength: bone material composition and bone structural design.
All fractures do not have the same pathogenesis or the same structural abnormalities that increase bone fragility. There are fractures that are associated with reduced bone mineral density (BMD) and others that are associated with reduced density of osteocytes, the key cell of bone remodeling.3 Patients who develop fractures may have different rates of bone remodeling that ranges from high to normal or low rates of remodeling. The heterogeneity of these mechanisms supports the notion that patients with fractures should not be treated in a similar way. Moreover, bone fragility is influenced by biomechanical parameters, such as the ultimate force, ultimate displacement, and energy absorption.3 However, what is happening in the bones of MGUS patients? Are there differences between patients with MGUS who develop fractures and those who do not? First of all, in the biochemical level, we know that MGUS patients have elevated bone resorption, assessed by the increased levels of N-telopeptide of collagen type I, one of the most accurate markers of bone resorption. This increase reflects the increased osteoclastic activity, which is driven by the elevation of the ratio of the major osteoclastogenesis factor, the receptor activator of nuclear factor κ-B ligand (RANKL) to osteoprotegerin (OPG).4 Indeed, the sRANKL/OPG ratio is higher in MGUS patients with fractures compared with those without fractures.5 Furthermore, circulating levels of dickkopf-1 are high at least in subsets of patients with MGUS, suggesting a bone formation inhibitory effect on these patients.6 MGUS patients with fractures are usually older (mean age, 63 years), with longstanding disease (>8 years) compared with those without fractures (60 years and 6 years after diagnosis), whereas their BMD of the lumbar spine, femoral neck, and total BMD is lower,5 and this is one of the main reasons of increased bone fragility in MGUS. High-resolution peripheral quantitative computed tomography (HRpQCT) volumetric BMD (vBMD) confirms the presence of alterations in the bone microarchitecture of MGUS patients.6
The reason for this defect is unknown to date. Axial skeleton is the major area of fractures in MGUS and cortical bone comprises approximately 80% of the axial skeleton or even more after the age of 65 years when MGUS is more prevalent. Cortical thinning and porosity reduces the resistance of bone to the propagation of cracks, initially by the development of microcracks and then by complete fractures.7 On the contrary, bone formation and the deposition of new bone reduces cortical porosity and focal stress, thereby preventing bone microdamage. The importance of cortical thinning and porosity in the fracture risk is reflected by the notion that a reduction of 1 standard deviation in cortical thickness is associated with a nearly threefold increased risk of fracture in healthy population.8 In the present brief report, the Mayo Clinic group used HRpQCT of the radius in 50 MGUS patients and 100 controls and showed that MGUS patients have higher cortical porosity with higher cortical pore volume and low vBMD compared with controls. Moreover, all parameters of bone strength (ie, failure load and stiffness) and mainly apparent modulus were lower in MGUS patients. Thus, this report reveals at least 2 major mechanical reasons for increased fragility in the bones of MGUS patients: increased cortical thinning and reduced bone strength. However, the report has some limitations: (1) the low number of patients cannot allow detection of differences between MGUS patients with and without fractures; (2) the lack of follow-up does not reveal the time of these bone microarchitecture alterations; and (3) the HRpQCT needs to be tested in other areas outside the radius. The International Myeloma Working Group (IMWG) suggests that the DXA scan should be considered for patients with MGUS due to the well-documented increased fracture risk in these patients.9 HRpQCT seems to be a valuable technique that may substitute the DXA scan in the future or give supplementary information in an attempt to recognize earlier MGUS patients with bone loss. However, this has to be proven in larger studies.
The IMWG also suggests bisphosphonates in all MGUS patients with proven osteopenia or osteoporosis.9 Indeed, bisphosphonates increase bone strength through decreasing bone turnover. This lower bone turnover results in a higher mineralization and lower number of active resorption pits within bone. The mechanisms of bone loss described in this report support the use of bisphosphonates in MGUS patients. Bisphosphonates have been used in MGUS patients and have increased the BMD of the patients, but we do not know if they manage to reduce the number of fragility fractures.10 If bisphosphonate therapy has to be given in all MGUS patients with HRpQCT alterations is unclear to date; further, the duration and frequency of bisphosphonates administration in MGUS patients has to be determined in large prospective studies.
Conflict-of-interest disclosure: The authors declare no competing financial interests.