Missing observations in bone histomorphometry on osteoporosis: Implications and suggestions for an approach

Crucial bone histomorphometric indices, i.e., turnover-related indices, are based on tetracycline double labeling. However, these indices are particul arly exposed to loss of information because of missing readings on double l abels. If the failure to make the observation is related to its magnitude, then selection bias may invalidate the conclusions. Therefore, ignoring mis sing double labels may lead to a selection of high-turnover patients. The a im of this study was to analyze the dimension and the impact of excluding i liac crest bone biopsies with missing readings in women with spinal crush f racture osteoporosis (n = 158, median 68 years, range 49-80 years). Further more, two different Lower limits of the mineral apposition rate (MAR) were examined to explore their usefulness as a biological minimum that can be us ed for cases with missing readings, i.e., recoding of missing values. The a verage MAR (calculated as the mean of all interlabel widths measured in eac h individual) shows a lower limit of 0.3 mu m/day, suggesting an apparent m inimum for the interlabel width (Ir.L.Wi) of 3-4 mu m Identifying the small est interlabel width measured in each individual and calculating the minima l MAR shows that 77% of the minimal MAR values are below 0.3 mu m/day and r each a minimum of 0.1 mu m/day, corresponding to an interlabel width of abo ut 1 mu m. Therefore, the minimal MAR presents a biological minimum of 0.1 mu m/day. This value is used for our recoding: if no labels are sampled (2% of our population), Ir.L.Wi is assigned the value 0; if none or an insuffi cient number of double labels are sampled (29% of our population), then Ir. L.Wi is assigned the value 1 mu m. Excluding cases with missing readings on any dependent variable increases the mineralizing surface (MS/BS) by 60% ( 2p < 0.01); other indices show no significant change, The suggested recodin g decreases the average MAR by 4% (2p < 0.01), prolongs the remodeling peri od by 19% (2p < 0.01), and tends to decrease the activation frequency (2p = 0.09), Furthermore, the number of excluded biopsies tends to be larger amo ng the older (2p = 0.09) and more severely osteopenic individuals (2p = 0.0 9), We conclude that ignoring missing double labels leads to selection bias ; therefore, specific measures such as recoding procedures are needed to al low proper representation of low turnover patients. There is also a risk of bias caused by the exclusion of the older, osteopenic patients in bone his tomorphometric osteoporosis trials, (C) 1999 by Elsevier Science Inc, All r ights reserved.