May Parisien

Resistance to Bone Resorbing Effects of PTH in Black Women

Black women have a lower incidence of vertebral and hip fractures than white women, possibly due to differences in skeletal and mineral metabolism. One suggested mechanism is that blacks have decreased skeletal sensitivity to parathyroid hormone (PTH). To test this hypothesis, we infused h(1–34)PTH in healthy premenopausal black (n = 15) and white (n = 18) women over 24 h and measured serum and urine indices of bone turnover and calcium metabolism throughout the infusion. At baseline, the mean 25‐hydroxyvitamin D (25(OH)D) concentration was significantly lower in black women (46%). There were also nearly significant trends toward higher PTH and lower urinary calcium and pyridinoline levels in black women. During infusion, there were no racial differences in the mean (1–34)PTH levels achieved or in resultant elevations of serum calcium or 1,25‐dihydroxyvitamin D (1,25(OH)2D) levels. Endogenous parathyroid suppression (measured by (1–84)PTH levels) was also similar between blacks and whites. There was an initial decline in urinary calcium/creatinine in both groups with a greater reduction in black women early in the infusion period (p < 0.05 at 8 h). Furthermore, blacks had lower levels of urinary calcium/creatinine throughout the infusion (p < 0.05 group difference). Bone formation markers (carboxy‐terminal propeptide of type I procollagen and osteocalcin) decreased within 8 h and continued to decline throughout the infusion with no distinguishable racial differences (p < 0.05 time trend for both). The most dramatic difference between black and white women in response to PTH infusion was represented by the bone resorption markers. Three separate metabolites of bone resorption (cross‐linked N‐telopeptide of type I collagen, cross‐linked C‐telopeptide of type I collagen, and free pyridinoline) all showed substantially greater elevations in white (mean peak increments 399, 725, and 43%) compared with black women (mean peak increments 317, 369, and 17%) during the infusion (p < 0.05 group differences for all three variables). These data strongly suggest that blacks have decreased skeletal sensitivity to the acute resorptive effects of increased PTH. This finding indicates that calcium homeostasis may be accomplished in blacks (during times of relative calcium deficiency) by greater conservation of calcium from nonskeletal sources (most likely renal) with relative preservation of skeletal tissue. These differences in calcium economy could account, at least in part, for the increased bone mass and lower incidence of osteoporotic fractures in black women.

Histomorphometric Assessment of Bone Mass, Structure, and Remodeling: A Comparison Between Healthy Black and White Premenopausal Women†

While noninvasive studies of bone mass and turnover in blacks and whites abound, histologic evaluations are very rare. We have performed a comparative bone histomorphometric study of iliac biopsies from 55 healthy, premenopausal women including 21 blacks (mean age 33.4 + 1.2 years) and 34 whites (mean age 32.5 + 0.8 years) of comparable age, weight, body composition, education, and lifestyle. Biochemical indices of mineral metabolism: parathyroid hormone, 25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D, serum ionized calcium, serum phosphorus, and urinary calcium/creatinine were measured in the fasting state. Blacks had lower 25‐hydroxyvitamin D (31.5 ± 3.36 vs. 63.21 ± 3.79 nmol/l, p = 0.0001). Histomorphometric indices of bone volume, structure, and connectivity were not different between groups. The following indices of bone remodeling were also similar in both groups: eroded perimeter, osteoid width, mineralizing perimeter, tissue‐based bone formation rate, osteoid maturation time, active formation period, and activation frequency. However, osteoid perimeter (black [B] = 15.85 ± 1.30 vs. white [W] = 9.49 ± 0.70%, p = 0.0002), osteoid area (B = 2.55 ± 0.32 vs. W = 1.39 ± 0.12%, p = 0.003), single‐labeled perimeter (B = 5.46 ± 0.54 vs. W = 4.04 ± 0.33%, p = 0.03), mineralization lag time (B = 38.18 ± 4.04 vs. W = 21.83 ± 1.60 days, p < 0.009), and total formation period (B = 148.15 ± 19.70 vs. W = 84.04 ± 7.62 days, p = 0.0056) were higher in blacks than in whites. The quiescent perimeter (B = 76.91 ± 1.40 vs. W = 84.25 ± 0.91%, p = 0.0001), mineral apposition rate (B = 0.70 ± 0.02 vs. W = 0.75 ± 0.02 μm/day, p = 0.066), mineralizing osteoid perimeter (B = 0.49 ± 0.04 vs. W = 0.75 ± 0.04%, p = 0.0001) and adjusted apposition rate (B = 0.35 ± 0.04 vs. W = 0.58 ± 0.04 μm3/μm2/day, p = 0.0001) were all lower in blacks than in whites. These results indicate that there are no differences in bone volume, microstructure, or turnover between black and white premenopausal women. However, there are significant differences in the mechanism of bone formation between the two groups, with a lower rate of mineralized matrix apposition within each remodeling unit and a longer total formation period in blacks than in whites. The differences appear to be the result of more frequent and/or longer inactive periods in the life span of the bone formation units in blacks. These differences may allow a greater overall deposition of bone mineral in black women and therefore help explain a higher bone mass and perhaps better bone quality in black than white women.

Tumor-induced osteomalacia : Clinical and basic studies

A patient with classic clinical and biochemical features of tumor‐induced osteomalacia (hypophosphatemia, phosphaturia, and undetectable serum concentrations of 1,25‐dihydroxyvitamin D [1,25(OH)2D]) was studied before and after resection of a benign extraskeletal chondroma from the plantar surface of the foot. Presurgical laboratory evaluation was notable for normal serum concentrations of calcium, intact parathyroid hormone (PTH), parathyroid hormone‐related protein (PTHrP), and osteocalcin, increased serum alkaline phosphatase activity, and frankly elevated urinary cyclic adenosine monophosphate (cAMP) and pyridinium cross‐link excretion. Quantitative histomorphometry showed severe osteomalacia and deep erosions of the cancellous surface by active osteoclasts. After resection, serum 1,25(OH)2D normalized within 24 h, while renal tubular phosphorus reabsorption and serum phosphorus did not normalize until days 2 and 3, respectively; serum Ca declined slightly, and serum intact PTH, osteocalcin, and urinary pyridinium cross‐link excretion increased dramatically. Urinary cAMP excretion declined immediately after resection and then began to increase concomitant with the increase in serum intact PTH. A second bone biopsy taken 3 months after resection demonstrated complete resolution of the osteomalacia, increased mineral apposition rate (1.09 μ/day), resorption surface (9.2%), mineralizing surface (71%), and bone formation rate (0.83 mm3/mm2/day), and marked decreases in cancellous bone volume (13.1%) and trabecular connectivity compared with the first biopsy. Tumor extracts did not affect phosphate transport in renal epithelial cell lines or 1α‐hydroxylase activity in a myelomonocytic cell line. The patients course suggests that the abnormal 1,25(OH)2D and phosphorus metabolism is due to a tumor product that may be acting via stimulation of adenylate cyclase activity. Increased bone resorption prior to surgical resection suggests that the tumor may also produce an osteoclast activator. The rise in resorption surface and pyridinium cross‐link excretion, increase in serum osteocalcin and bone mineralization, normalization of osteoid width, and fall in cancellous bone volume after resection are consistent with healing of osteomalacia by rapid remodeling.

Trabecular Architecture in Iliac Crest Bone Biopsies: Infra-individual Variability in Structural Parameters and Changes with Age

A histomorphometric study was conducted on bilateral iliac crest samples obtained at autopsy from 27 subjects who had died suddenly. Six parameters related to cancellous bone structure were measured: bone volume (BV/TV), surface density (BS/TV), surface/volume ratio (BS/BV), trabecular thickness (Tb.Th.), trabecular number (Tb.N), and trabecular separation (Tb.Sp). There were no significant differences between right and left sides in the mean values for each parameter. However, when subjects were considered individually, there was a substantial difference in the majority of cases for all parameters. The intra-individual variation (IIV) was calculated for each subject as the percentage deviation from the mean for the two sides. There was a wide range in IIV (0.05-30.27%) with a mean value of approximately 11.5% for each parameter. In males the mean IIV ranged from 9 to 11% and from 14 to 16% in females. The IIV in BV/TV was positively correlated with age. Data generated on a subsample of 15 males were used to predict patient group sizes required to detect minimum significant differences in studies involving repeat biopsies. Sample sizes of 32, 16, and 8 patients would be required for relative increments in BV/TV of 29, 36, and 46%, respectively, to be statistically significant. Tb.Sp increased significantly with age but there was no significant change in Tb.Th. This supports the view that bone loss with aging occurs primarily through a mechanism involving complete disappearance of individual trabecular plates.

Relationships between quantitative histological measurements and noninvasive assessments of bone mass

We performed a comprehensive analysis of the relationships between histologic indices in the iliac crest (cancellous bone volume, trabecular structural indices, cortical width, and core width) and bone density in the spine, hip, and wrist in 81 patients with various metabolic bone diseases including osteoporosis, osteomalacia, hyperparathyroidism, and Pagets disease. In the whole group, all of the histologic indices correlated significantly with bone mineral density (BMD) of the spine and the three regions of the hip (r = 0.28-0.73), with the exception of cortical width which correlated with the hip but not the spine (r = 0.21). There was no relationship between the histologic variables and either the distal or proximal radius. When the osteoporotic subgroup was considered separately, the relationships between BMD and both cancellous bone volume and the structural indices (trabecular number, separation, and thickness) were lost. In contrast, cortical width correlated more strongly with both spine and hip BMD. The relationship between core width and the spine was lost but persisted in the hip region. In female osteoporotic patients alone, only cortical width remained significantly correlated with spine or hip BMD. We conclude that the relationships between bone densities in the axial and peripheral regions and histomorphometric variables in iliac crest are not constant. In addition, cancellous bone volume and the trabecular structural indices relate well to noninvasive axial BMD measurements only in a heterogenous group with a large variance in both parameters. In the more homogeneous group with osteoporosis, cortical width appears to be a more powerful predictor of BMD at the important sites of osteoporotic fracture.

CHAPTER 26 – Histomorphometric Analysis of Bone in Primary Hyperparathyroidism

Bone histomorphometry allows accurate evaluation not only of bone mass and turnover but also of bone microarchitecture Microscopic examination of bone biopsied from the iliac crest after in vivo tetracycline labeling permits separate assessments of cortical and cancellous bone, a clear advantage over noninvasive methods of bone mass measurement, which can provide only indirect information in this regard. This technique has clinical applications in selected disorders— such as primary hyperparathyroidism, where it allows the detection of abnormalities of bone turnover, even in asymptomatic subjects showing no radiologic evidence of bone disease. In spite of limitations inherent in the small size of the biopsy sample and regional variations among skeletal sites, the iliac crest site is generally considered to represent both the structure and the metabolic processes that affect the entire skeleton. A histomorphometric study confirmed the accelerated rate of bone remodeling in primary hyperparathyroidism. In a group of subjects with mild primary hyperparathyroidism, there was a two to three fold increase in the values of static and dynamic turnover indices.

Tuberculous Arthritis in Children: Diagnosis by Needle Biopsy of the Synovium

In two children ages 8 months and 4 years, tuberculous synovitis of the knee was suggested by pathologic examination of synovial tissue obtained through needle biopsy. Culture of the biopsy material was positive for Mycobacterium tuberculosis in one case. In this child, the tuberculin test was negative, in the absence of anergy, at the time the child was first evaluated, and the primary lung lesion was not identified by the radiologist.Tuberculous synovitis has not previously been recognized as part of primary tuberculosis during the early weeks when the tuberculin skin test may be negative. Magnetic resonance imaging (MRI) is a sensitive modality for demonstrating joint fluid, synovial hypertrophy, and associated osteomyelitis, if present. With the increasing frequency of cases of tuberculosis in the population, greater awareness of the risk of tuberculous arthritis in childhood is important in order to recognize this unusual presentation. If negative early on, the tuberculin skin test should be repeated after 6 weeks of arthritis. A needle biopsy of the synovium is helpful and appropriate in all children with monoarticular arthritis who have a positive tuberculin skin test.

Gross and Histological Analysis of Healing After Dog Flexor Tendon Repair with the Teno Fix™ Device

The purpose of this study was to examine the in vivo characteristics of the stainless-steel Teno Fix™ device used for flexor tendon repair. The common flexor digitorum superficialis tendon was transected in 16 dogs and repaired with the device. The animals were euthanized at 3, 6, or 12 weeks postoperatively. Difficulties with cast immobilization led nine of 16 animals to be full weight bearing too early, leading to rupture of their repairs. The seven tendons with successful primary repairs (gap <2 mm) underwent histological examination. This in vivo study demonstrates that use of the Teno Fix™ in “suture” of dog flexor tendons did not lead to scarring at the tendon surface, does not cause an inflammatory reaction within the tendon and does not interfere with tendon healing.

Novel translocation (9;12)(q22;q24) in secondardy chondrosarcoma arising from hereditary multiple exostosis

We report a new translocation in a patient with a history of hereditary multiple exostosis (HME) who developed a recurrent grade I chondrosarcoma involving the sacrum and retroperitoneum. Karyotypic analysis of the tumor revealed a sole chromosome abnormality t(9;12)(q22;q24.3). To our knowledge, this translocation has not been previously identified in either chondrosarcoma, HME, or related tumor types. Our novel translocation may be related to the sarcomatous degeneration of the pre-existing exostosis.

Magnetic resonance imaging depiction of tight iliotibial band in melorheostosis associated with severe external rotation deformity, limb shortening and patellar dislocation in planning surgical correction

We present the case of a 14-year-old male with melorhesotosis and severe iliotibial band tightness which was associated with femoral shortening, severe external rotational deformity of the femur, genu valgum and patellar dislocation in the right lower extremity. Skeletal survey revealed irregular radiodense streaks involving the pelvis, femoral head, femoral shaft, distal femoral epiphysis, talus and middle phalangeal bones of the foot. Magnetic resonance (MR) imaging showed thickening of the iliotibial band in addition to low MR signal changes in the bone. Intraoperatively fibrosis in the subcutaneous layer and a thickened iliotibial band were found. MR images were very useful in understanding the soft tissue pathoanatomy in melorheostosis and planning surgical correction.