Previous studies have demonstrated that histomorphometric indices of trabecular bone micro-architecture were more favorable in patients undergoing arthroplasty for hip osteoarthritis than in patients with hip fracture, as well as in comparison with age-matched subjects [
22‐
25]. In this study, bone PEN levels, considered surrogate markers of quality of organic bone matrix, were measured to assess another determinant of strength of bone, the bone tissue material properties. To our knowledge, this is the first study comparing serum and bone pentosidine levels in patients with low-impact hip fractures and in patients with advanced osteoarthritis. Our patients with hip fractures had higher serum and bone PEN concentrations than those with advanced stages of hip osteoarthritis. Previously, PEN content in cortical and trabecular bone of patients with femoral neck fractures has been shown to be higher than in those of age-matched controls [
18,
26]. However, the proof of the association between the risk of hip fractures and serum and bone PEN levels would require further studies, considering also bone microarchitecture, bone mineral density (BMD), clinical factors of risk of fracture and namely the general frailty of hip fracture patients should be considered [
27,
28].
The association between bone PEN and fracture risk appears independent of BMD mainly in type-I diabetes [
29‐
31]. Also, using an Enzyme-Linked ImmunoSorbent Assay (ELISA), the association between serum PEN levels and changes in BMD in patients treated with bisphosphonate was not confirmed [
32]. However, in Japanese postmenopausal women, only a moderate BMD-independent association between urinary PEN and the incidence of vertebral and non-vertebral fractures was observed [
28,
33,
34]. In the French OFELY study, there was a significant association between urinary PEN and the risk of all fractures in 396 healthy postmenopausal women, although, the odds ratio was not significant after adjustment for BMD [
35].
This study has several limitations. First, the results in our patients must be interpreted within the context of differences in age and body weight, as well as the admitted risk factors for hip osteoarthritis, hip osteoporosis and fractures, although our results were adjusted for age, sex, weight, serum creatinine, and diabetes. The increasing trend in serum and bone PEN levels with age, which were observed in this study, was in accordance with that seen in other studies using HPLC [
10], or ELISA [
5,
36,
37]. Second, for ethical reasons, bone PEN levels in our patients were not compared with those in healthy age matched subjects from the general population. There was limited data on the differences between PEN levels in osteoarthritis and in healthy subjects, except for an observation that found no significant differences in plasma PEN levels in 17 patients with osteoarthritis compared with controls [
19]. Previously, we reported that in patients with knee osteoarthritis, PEN serum concentrations were increased compared with healthy controls, and correlated with a cartilage destruction marker (cartilage oligomeric matrix protein) in synovial fluid [
38]. However, knee osteoarthritis is mostly hypertrophic while in the majority of our patients, hip osteoarthritis was mostly of the atrophic type. Thus, although the interpretation of serum PEN levels in patients with knee and hip osteoarthritis and hip fracture should be done with caution, pentosidine crosslinking can nonetheless be considered as a measure of local bone age. Accordingly, serum PEN levels were higher in osteoporotic patients with long term aminobisphosphonate treatment than in BMD-matched controls [
39]. Pentosidine formation is closely linked not only to glycation but also to oxidative processes [
40,
41]. Accumulation of advanced non-enzymatic glycation end products in numerous body tissues during the course of aging, in diabetes, and in rheumatoid arthritis has been associated with oxidative stress [
13]. It remains unknown whether the increase in AGE modified proteins in patients with chronic inflammation merely represents oxidative stress or they actively participate in bone and joint destruction [
19]. Also, it is unclear to what extent serum PEN contributes to bone strength at fractured sites, since bone fractures are strain-controlled and PEN affects the organic matrix, which is better known as a contributor to post-yield deformation of bone rather than to its elastic properties [
9]. Third, PEN has been shown to be also secreted from tissues other than bone and it is unclear what proportion of serum PEN levels actually reflects PEN content in bone. Compared with controls, PEN levels are significantly increased not only in aging, osteoporosis, diabetes mellitus, renal disorders, and rheumatoid arthritis [
4,
5,
42‐
45], but have also been reported to correlate with the radiographic severity of lumbar spondylosis without vertebral fractures [
46]. Increased serum PEN was an independent risk factor for loss of muscle mass in postmenopausal women with type 2 diabetes [
47]. Finally, BMD measurements or histomorphometry of tetracycline labeled bone could not be performed in our patients with incident hip fractures, or those undergoing arthroplasty for hip osteoarthritis. Serum markers such as type 1 collagen cross-linked C-telopeptide (βCTX) and procollagen type I amino-terminal propeptide (PINP) were not measured in our patients, since both markers are strongly affected by incident fractures. These markers reflect whole body rates of bone resorption and bone formation rather than the rates of remodeling at specific skeletal sites containing different ratios of trabecular to cortical component, each with its own metabolic rates [
48].