Shijing Qiu

In vivo diffuse damage in human vertebral trabecular bone

Accumulation of microdamage in vivo may lead to loss of bone quality. Until recently, linear microcracks were the only known form of in vivo microdamage, but through the use of confocal microscopy an additional level of damage (diffuse damage) has been identified. In this study, in vivo diffuse damage was characterized and quantified in human vertebral trabecular bone as a function of tissue morphology, age, race, gender, and previously quantified in vivo linear microcracks. Presence of diffuse damage in human vertebral tissue was confirmed and validated by simultaneous use of polarized, ultraviolet, and laser confocal microscopy. Diffuse damage was found to occur preferentially within trabecular packets rather than in interstitial bone (p < 0.05). It was consistently higher in men compared with women (p < 0.05), but was not different by race or age group. Diffuse damage did not correlate with linear microcracks, but both exhibited the same probability distribution in which the percentage of individuals having a particular amount of damage decreased exponentially as damage content increased. These findings suggest that diffuse damage accumulation and repair are governed by the same biological phenomena as microcracks, but diffuse damage contributes independently to the microdamage content of bone.

Reduced Iliac Cancellous Osteocyte Density in Patients With Osteoporotic Vertebral Fracture

Iliac cancellous osteocyte density declines with age, but its relationship to vertebral fracture pathogenesis is unknown. We performed iliac bone biopsy in 44 women with clinical vertebral fracture and 56 healthy women. The fracture patients had 34% fewer osteocytes but no reduction in percent occupied lacunae. Some patients destined to sustain vertebral fracture make cancellous bone with fewer osteocytes.

Age and distance from the surface but not menopause reduce osteocyte density in human cancellous bone

Previous studies of osteocyte density in human cancellous bone have relied mainly on autopsy samples and have demonstrated an age-related decline in men, but there are insufficient data in women. Using previously obtained transiliac bone biopsies from 94 healthy white women, aged 20-73 years, 38 premenopausal and 56 postmenopausal, we measured osteocytes and lacunae in ten randomly selected areas using 5-microm-thick sections stained with Goldner trichrome. For each subject, the number of osteocytes (Ot.N/B.Ar), empty lacunae (EL.N/B.Ar), and total lacunae (Tt.L.N/B.Ar) per bone area, and the proportion of occupied lacunae (Ot.N/Tt.L.N), were calculated. In 92 cases the measurements were made separately in superficial bone (<25 microm from the surface) and in deep bone (>45 microm from the surface). Mean values and differences between extreme values (DEV) for each variable were computed from the ten measured areas. In addition, confocal microscopic examination was performed on 100 microm sections. We found that Ot.N/B.Ar, Tt.L.N/B.Ar, and Ot.N/Tt.L.N decreased, but EL.N/B.Ar increased significantly with age (p < 0.001). The rates of decline were most rapid initially, falling exponentially with increasing age; the linear regressions for all four variables were significant in premenopausal, but not postmenopausal, women. At all ages, there were significantly more osteocytes in superficial than in deep bone; there was no significant decline with age in superficial bone, but a steeper exponential decline in deep bone than in whole trabeculae. DEV did not change with age for any variable. Confocal images revealed that the morphology of the osteocyte network was heterogeneous in different regions and trabeculae. The trabeculae with lower osteocyte density contained acellular areas, especially in interstitial bone. We conclude: (1) osteocyte density declines with age in women as it does in men; (2) the decline occurs exclusively in deep bone, not in superficial bone, suggesting that it is the age of the bone rather than the age of the subject that is important; (3) the rate of age-related decline falls exponentially with age and is not significant in postmenopausal women alone; (4) except for the differences between superficial and deep bone, the pattern of osteocyte distribution within and between trabeculae was not affected by age or menopause; and (5) the data raise the possibility that one function of remodeling in iliac cancellous bone is to maintain osteocyte viability.

Relationships between osteocyte density and bone formation rate in human cancellous bone

Iliac cancellous osteocyte density decreases with age in deep bone but not in superficial bone, most likely because of remodeling. It has been suggested that osteocytes can inhibit bone remodeling. Accordingly, we examined the relationship between osteocyte density and bone formation rate in 92 healthy women. In superficial bone (<25 microm from the surface), we found a weak but significant (p < 0.03) inverse correlation between BFR/BS and Ot. N/B.Ar that was unaffected by menopause and independent of age. A weaker positive relationship with empty lacunar density improved significance. The data appear to suggest a negative feedback loop, but osteocytes explain only 10% of the variance in BFR/BS, and 97% of the variance in osteocyte density is explained by total lacunar density. This measure of initial osteocyte density during bone formation has a high coefficient of variation (20%) indicating large individual differences. We conclude that: (1) our data support the proposal that osteocytes can inhibit bone remodeling; (2) osteocyte density in superficial bone depends mainly on initial osteocyte density during bone formation and is maintained but not regulated by bone remodeling; and (3) the inverse relationship between BFR/BS and osteocyte density may reflect the homeostatic need to maintain calcium exchangeability in the lining cell-osteocyte syncytium.

Dependence of bone yield (volume of bone formed per unit of cement surface area) on resorption cavity size during osteonal remodeling in human rib: implications for osteoblast function and the pathogenesis of age‐related bone loss

It is both a necessary and a sufficient condition for bone to be lost with age at any surface location that during remodeling the replacement of resorbed bone is incomplete. In both the ilium and the rib, the degree of such focal imbalance is smaller on the intracortical than on the endocortical or cancellous surfaces that are adjacent to bone marrow. The reason for this difference is unknown. To further examine this question, we measured various geometric variables in 1263 osteons in rib cross sections from 65 persons, including both sexes and age ranges 20 to 30 years and 60 to 70 years (four groups). Haversian canal (HC) area did not differ significantly between sexes or age groups. Percent osteonal refilling was close to 95% in all groups and did not differ between sexes but fell slightly with age. There was a very highly significant linear relationship between osteon bone area and (osteon area + HC area) in all groups, with coefficients of determination (r2) greater than 0.98. The regression slopes declined slightly with age in women but not in men. There was a very highly significant quadratic relationship between osteon bone area and osteon perimeter in all groups, with r2 values greater than 0.97. The ratio osteon bone area:osteon perimeter, an index of bone yield—the volume of bone deposited on each unit area of cement surface—was strongly related to osteon area and did not differ between sexes but was slightly less in the older groups. We conclude the following: (1) The high efficiency of intracortical remodeling in the rib is confirmed, with only trivial effects of age. (2) For HC area to be maintained within narrow limits and bone balance preserved, either initial osteoblast density or osteoblast capacity (the two determinants of bone yield) or, most likely, both must increase progressively with the size of the resorption cavity, suggesting that osteoblast recruitment (relative to available surface) and osteoblast lifespan increase with the volume of bone resorbed. (3) Intracortical remodeling in the rib is more efficient than marrow‐adjacent remodeling at any site, possibly because of the different relationships to the circulation. In osteonal remodeling, all molecules released from resorbed bone must travel past the sites of osteoblast recruitment and operation, but in hemiosteonal remodeling, some molecules may not be subject to this constraint. (4) If marrow‐adjacent remodeling became as efficient as rib intracortical remodeling, age‐related bone loss would cease to be an important medical problem.

Scaling of Haversian canal surface area to secondary osteon bone volume in ribs and limb bones

Studies of secondary osteons in ribs have provided a great deal of what is known about remodeling dynamics. Compared with limb bones, ribs are metabolically more active and sensitive to hormonal changes, and receive frequent low-strain loading. Optimization for calcium exchange in rib osteons might be achieved without incurring a significant reduction in safety factor by disproportionally increasing central canal size with increased osteon size (positive allometry). By contrast, greater mechanical loads on limb bones might favor reducing deleterious consequences of intracortical porosity by decreasing osteon canal size with increased osteon size (negative allometry). Evidence of this metabolic/mechanical dichotomy between ribs and limb bones was sought by examining relationships between Haversian canal surface area (BS, osteon Haversian canal perimeter, HC.Pm) and bone volume (BV, osteonal wall area, B.Ar) in a broad size range of mature (quiescent) osteons from adult human limb bones and ribs (modern and medieval) and various adult and subadult non-human limb bones and ribs. Reduced major axis (RMA) and least-squares (LS) regressions of HC.Pm/B.Ar data show that rib and limb osteons cannot be distinguished by dimensional allometry of these parameters. Although four of the five rib groups showed positive allometry in terms of the RMA slopes, nearly 50% of the adult limb bone groups also showed positive allometry when negative allometry was expected. Consequently, our results fail to provide clear evidence that BS/BV scaling reflects a rib versus limb bone dichotomy whereby calcium exchange might be preferentially enhanced in rib osteons.

Independent and combined contributions of cancellous and cortical bone deficits to vertebral fracture risk in postmenopausal women

Using iliac bone histomorphometry on 78 patients with vertebral fracture and 66 healthy postmenopausal women, cortical thickness discriminated at least as well as any cancellous bone structural index between the two groups. Subjects with a deficit in both cortical and cancellous bone had much greater likelihood of fracture.

Abnormal bone remodeling in patients with spontaneous painful vertebral fracture.

The application of tetracycline‐based iliac bone histomorphometry to the study of the pathogenesis of osteoporosis has given conflicting results. Accordingly, we performed this procedure in 78 postmenopausal white women with one or more vertebral fractures identified according to rigorous criteria that excluded other causes of vertebral deformity and 66 healthy postmenopausal white women recruited from the same geographic region; the groups did not differ in age or weight. In each subject, measurements were made separately on the cancellous (Cn), endocortical (Ec), and intracortical (Ct) subdivisions of the endosteal envelope. In the fracture patients, osteoblast surface was reduced substantially on each subdivision, most markedly on the Cn surface, where about 25% of the deficit was in cuboidal (type II) osteoblasts, suggesting impaired recruitment; the remaining 75% of the deficit was in intermediate (type III) cells, suggesting earlier transition from type III to type IV (flat) cells. On the Ec and Ct surfaces, the deficit was exclusively in type III cells. Mean bone formation rate was reduced by about 18% on the Cn but not on the Ec or Ct surfaces. The deficit was more significant in subjects matched for Cn BV/TV when adjusted for the inverse regression on osteocyte density and after logarithmic transformation. The difference in bone formation rate resulted from a corresponding reduction in wall thickness without a change in activation frequency. The frequency distribution of bone formation rate was more skewed to the left in the fracture patients than in the controls. Osteoclast surface was significantly lower on each subdivision. The variation in osteoblast surface, bone formation rate, and osteoclast surface was significantly greater in the fracture patients than in the controls, with more abnormally low and abnormally high values. The data suggest the following conclusions: (1) The histologic heterogeneity of postmenopausal osteoporosis is reaffirmed; (2) the different subdivisions of the endosteal envelope, although in continuity, behave differently in health and disease; (3) a combination of defective osteoblast recruitment and premature osteoblast apoptosis would account for the deficit in type II and III cells and the reductions in wall thickness and bone formation rate on the Cn surface and the previously reported osteocyte deficiency in Cn bone; (4) premature disaggregation of multinuclear to mononuclear resorbing cells could account for the osteoclast deficit; and (5) some patients with vertebral fracture have one or another disorder of bone remodeling that at present cannot be identified by noninvasive means.

Analysis of the Effect of Osteon Diameter on the Potential Relationship of Osteocyte Lacuna Density and Osteon Wall Thickness

An important hypothesis is that the degree of infilling of secondary osteons (Haversian systems) is controlled by the inhibitory effect of osteocytes on osteoblasts, which might be mediated by sclerostin (a glycoprotein produced by osteocytes). Consequently, this inhibition could be proportional to cell number: relatively greater repression is exerted by progressively greater osteocyte density (increased osteocytes correlate with thinner osteon walls). This hypothesis has been examined, but only weakly supported, in sheep ulnae. We looked for this inverse relationship between osteon wall thickness (On.W.Th) and osteocyte lacuna density (Ot.Lc.N/B.Ar) in small and large osteons in human ribs, calcanei of sheep, deer, elk, and horses, and radii and third metacarpals of horses. Analyses involved: (1) all osteons, (2) smaller osteons, either ≤150 μm diameter or less than or equal to the mean diameter, and (3) larger osteons (>mean diameter). Significant, but weak, correlations between Ot.Lc.N/B.Ar and On.W.Th/On.Dm (On.Dm = osteon diameter) were found when considering all osteons in limb bones (r values −0.16 to −0.40, P < 0.01; resembling previous results in sheep ulnae: r = −0.39, P < 0.0001). In larger osteons, these relationships were either not significant (five/seven bone types) or very weak (two/seven bone types). In ribs, a negative relationship was only found in smaller osteons (r = −0.228, P < 0.01); this inverse relationship in smaller osteons did not occur in elk calcanei. These results do not provide clear or consistent support for the hypothesized inverse relationship. However, correlation analyses may fail to detect osteocyte‐based repression of infilling if the signal is spatially nonuniform (e.g., increased near the central canal). Anat Rec,, 2011.

Deliberate Total Parathyroidectomy: A Potentially Novel Therapy for Tumor-Induced Hypophosphatemic Osteomalacia

BACKGROUND Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic metabolic bone disorder that can be cured by removing or ablating the offending tumor. However, when the tumor cannot be localized, lifelong therapy with oral phosphate and calcitriol or cinacalcet with close monitoring is required. CASE REPORT A 56-year-old man was diagnosed with TIO in 1990. Initial therapy consisted of oral phosphate and calcitriol with symptomatic and biochemical improvement and healing of osteomalacia. Eight years later, hypercalcemic hyperparathyroidism developed, requiring subtotal parathyroidectomy with a transient increase in serum phosphate and normalization of serum calcium and PTH. Recurrent hypercalcemic hyperparathyroidism developed after 10 years of medical therapy. A deliberate total parathyroidectomy produced a prompt rise in serum phosphate into the normal range > 3.0 mg/dL and remained normal during the next 4 years of follow-up, despite continued very high serum fibroblast growth factor-23 levels throughout the 23-year follow-up. CONCLUSION We report an unusual case of a TIO patient with long-term follow-up who developed recurrent hypercalcemic hyperparathyroidism on long-term oral phosphate therapy. Deliberate total parathyroidectomy normalized serum phosphate despite persistently elevated fibroblast growth factor-23 levels. Total parathyroidectomy offers a potentially novel therapy in some patients with TIO in whom medical therapy is not feasible or the tumor is unresectable.