Preserved three-dimensional cancellous bone structure in mild primary hyperparathyroidism

By conventional 2-dimensional, histomorphometric analysis, we and others have previously shown that cancellous bone architecture is preserved in mild primary hyperparathyroidism (PHPT). We have now extended these observations to a 3-dimensional analysis using microcomputed tomography (microCT). Iliac crest bone biopsies were analyzed from the following subjects with PHPT: 22 postmenopausal women; 7 premenopausal women; similar numbers of normal pre- and postmenopausal women served as controls. Fifteen men with PHPT were also studied. Postmenopausal women with PHPT demonstrated features of preserved cancellous bone as shown by smaller age-related declines in cancellous bone volume (BV/TV) and connectivity density (Conn.D) and no change in bone surface/total volume (BS/TV) as compared to normal women. In postmenopausal women with PHPT, cancellous bone volume (BV/TV), bone surface/total volume, and connectivity density (Conn.D) were all higher, and trabecular separation (Tb.Sp) was lower than in postmenopausal controls. In sharp contrast to the findings in normal women, no structural variables in PHPT women were correlated with age. Also of note, there was no difference in any 3-dimensional index between women and men with PHPT. We conclude that three-dimensional, cancellous bone microarchitecture is preserved in patients with mild primary hyperparathyroidism.     

原发性甲状旁腺机能亢进症引起的全身多发性骨吸收

目的早期诊断和治疗原发性甲状旁腺机能亢进症引起的多发性骨吸收。方法回顾性分析1997年4月～2001年4月以多发性骨病变收入院的4例和外院会诊的1例原发性甲状旁腺机能亢进症患者的临床资料,其中男1例,女4例;年龄25～46岁,平均37岁。从发病至确诊的时间最长36个月,最短8个月,平均19.5个月。1例患者曾在当地医院行骨病变活检术,但未能早期确诊。所有患者疼痛均较严重,需服用强效止痛药物。大部分患者都有乏力、精神不振、食欲低下、胃肠不适等症状。同位素骨扫描显示全身骨骼多发核素异常浓聚区,X线片显示多发的颅骨、肋骨、骨盆及四肢骨吸收。实验室检查:血钙2.27～3.22mmol/L,甲状旁腺素168～214ng/ml。3例患者颈部能触及肿块,2例触诊正常。所有患者均转入普通外科。结果甲状旁腺切除术后病理确诊为原发性甲状旁腺机能亢进症,其中甲状旁腺腺瘤3例,甲状旁腺组织增生2例。甲状旁腺切除术后患者的全身疼痛均减轻。随访3～27个月,平均15个月。随访时患者原有骨吸收区域都有不同程度的钙化和缩小。结论在临床上,对于以全身多发骨病变就诊于骨科的较年轻患者,应考虑原发性甲状旁腺机能亢进性骨病的可能。确诊后,应及时切除异常甲状旁腺,避免骨吸收的进一步加重。     

Osteosarcoma of bone in apatient with primary hyperparathyroidism: a case report.

A 69-year-old woman was diagnosed with a malignant tumor of the right proximal femur. She had primary hyperparathyroidism and chronic elevation of parathyroid hormone levels (PTH > 1,000 pg/ml). She underwent resection of the bone lesion; histological analysis showed a high-grade fibroblastic osteosarcoma. In addition, she underwent curative resection of a large left superior parathyroid adenoma. To our knowledge, this is the third reported clinical case of osteosarcoma arising in association with hyperparathyroidism.     

Primary hyperparathyroidism: changes in trabecular bone remodeling following surgical treatment--evaluated by histomorphometric methods

Iliac bone biopsies from 11 patients who underwent successful surgery for primary hyperparathyroidism were examined before and median 7 months after surgical treatment. Trabecular bone volume increased (p less than 0.05) and eroded (p less than 0.005) and osteoid covered surfaces decreased (p less than 0.005) in the postoperative period. Also, a decline in tetracycline labeled surfaces was noticed (p less than 0.02). Osteoid thickness, mineral appositional rate and mineralization lag time were unchanged. Bone formation rate at the level of the basic multicellular unit (BMU) was unaffected, but at the tissue level bone formation rate diminished (p less than 0.02). The surgical cure of primary hyperparathyroidism was found accompanied by a change in bone metabolism as the trabecular bone remodeling decreased from a high turnover to a low turnover state. The spongy bone mass increased after parathyroidectomy but the clinical significance of this finding was not clear.     

Fatigue-induced microdamage in cancellous bone occurs distant from resorption cavities and trabecular surfaces

Impaired bone toughness is increasingly recognized as a contributor to fragility fractures. At the tissue level, toughness is related to the ability of bone tissue to resist the development of microscopic cracks or other tissue damage. While most of our understanding of microdamage is derived from studies of cortical bone, the majority of fragility fractures occur in regions of the skeleton dominated by cancellous bone. The development of tissue microdamage in cancellous bone may differ from that in cortical bone due to differences in microstructure and tissue ultrastructure. To gain insight into how microdamage accumulates in cancellous bone we determined the changes in number, size and location of microdamage sites following different amounts of cyclic compressive loading. Human vertebral cancellous bone specimens (n = 32, 10 male donors, 6 female donors, age 76 ± 8.8, mean ± SD) were subjected to sub-failure cyclic compressive loading and microdamage was evaluated in three-dimensions. Only a few large microdamage sites (the largest 10%) accounted for 70% of all microdamage caused by cyclic loading. The number of large microdamage sites was a better predictor of reductions in Young’s modulus caused by cyclic loading than overall damage volume fraction (DV/BV). The majority of microdamage volume (69.12 ± 7.04%) was located more than 30 μm (the average erosion depth) from trabecular surfaces, suggesting that microdamage occurs primarily within interstitial regions of cancellous bone. Additionally, microdamage was less likely to be near resorption cavities than other bone surfaces (p < 0.05), challenging the idea that stress risers caused by resorption cavities influence fatigue failure of cancellous bone. Together, these findings suggest that reductions in apparent level mechanical performance during fatigue loading are the result of only a few large microdamage sites and that microdamage accumulation in fatigue is likely dominated by heterogeneity in tissue material properties rather than stress concentrations caused by micro-scale geometry.     

Effect of concomitant vitamin D deficiency or insufficiency on lumbar spine volumetric bone mineral density and trabecular bone score in primary hyperparathyroidism

Summary

Lower vitamin D and higher parathyroid hormone (PTH) levels are associated with higher volumetric BMD and bone strength at the lumbar spine as measured by central quantitative computed tomography in primary hyperparathyroidism (PHPT), but there are no differences in bone microarchitecture as measured by trabecular bone score (TBS).

Introduction

The purpose of this study was to evaluate the association between 25-hydroxyvitamin D (25OHD) and volumetric bone mineral density (vBMD) and the TBS at the lumbar spine (LS) in PHPT.

Methods

This is a cross-sectional analysis of PHPT patients with and without low 25OHD. We measured vBMD with quantitative computed tomography (cQCT) and TBS by dual-energy X-ray absorptiometry (DXA) at the LS in 52 and 88 participants, respectively.

Results

In the cQCT cohort, those with lower vitamin D (<20 vs. 20-29 vs. ≥30 ng/ml) tended to be younger (p?=?0.05), were less likely to use vitamin D supplementation (p?<?0.01), and had better renal function (p?=?0.03). Those with 25OHD <20 ng/ml had 80 and 126 % higher serum PTH levels respectively vs. those with 25OHD 20–29 ng/ml (p?=?0.002) and 25OHD ≥30 ng/ml (p?<?0.0001). Covariate-adjusted integral and trabecular vBMD were higher in those with 25OHD 20–29 vs. those with 25OHD ≥30 ng/ml, but those with 25OHD <20 did not differ. Because there were few participants with 25OHD deficiency, we also compared those with vitamin D <30 vs. ≥30 ng/ml. Covariate-adjusted integral and trabecular vBMD were 23 and 30 % higher respectively (both p?<?0.05) in those with vitamin D <30 vs. ≥30 ng/ml. TBS was in the partially degraded range but did not differ by vitamin D status.

Conclusion

In mild PHPT, lower 25OHD is associated with higher PTH, but vitamin D deficiency and insufficiency using current clinical thresholds did not adversely affect lumbar spine skeletal health in PHPT. Further work is needed to determine if higher vBMD in those with lower vitamin D is due to an anabolic effect of PTH.

     

Effect of slow-release sodium fluoride on cancellous bone histology and connectivity in osteoporosis

We have previously demonstrated that a treatment regimen of slow-release sodium fluoride (SRNaF) and continuous calcium citrate increases lumbar bone mass, improves cancellous bone material quality, and significantly reduces vertebral fracture rate in osteoporotic patients. In order to assess whether such treatment also improves trabecular structure, we quantitated cancellous bone connectivity before and following 2 years of therapy with SRNaF in 23 patients with osteoporosis and vertebral fractures. In addition, we performed bone histomorphometry on the same sections used for connectivity measurements. There was a significant increase in L2-L4 bone mineral density during therapy (0.827 ± 0.176 g/cm² SD to 0.872 ± 0.166, p = 0.0004). Significant histomorphometric changes were represented by increases in mineral apposition rate (0.6 ± 0.4μm/d to 1.1 ± 0.7, p = 0.0078) and adjusted apposition rate (0.4 ± 0.3 μm/d to 0.6 ± 0.4, p = 0.016). On the other hand, trabecular spacing significantly declined (from 1375 ± 878 μm to 1052 ± 541, p = 0.05). Two-dimensional quantitation of trabecular struts on iliac crest histological sections disclosed significant increases in mean node number per mm² of cancellous tissue area (0.22 ± 0.12 vs. 0.39 ± 0.27, p = 0.0077), the mean node to free-end ratio (0.23 ± 0.21 vs. 0.41 ± 0.46, p < 0.05), and in the mean node to node strut length per mm² of cancellous area (0.098 ± 0.101 vs. 0.212 ± 0.183, p < 0.01). There were no significant changes in any of the measurements associated with free-end number or free-end to free-end strut length. When patients were divided into those with severe and mild-modest spinal bone loss (based upon initial lumbar bone density) the significant changes in connectivity occurred in patients with mild-moderate bone loss, but not in those with severe bone loss, suggesting that fluoride's effect is in part dependent on the presence of a certain critical amount of bone. This finding in combination with the previously reported increases in bone mass and bone material quality may explain the significant reduction in vertebral fracture rate observed with this particular fluoride regimen.     

Increased femoral neck cancellous bone and connectivity in coxarthrosis (hip osteoarthritis)

Patients with coxarthrosis (cOA) have a reduced incidence of intracapsular femoral neck fracture, suggesting that cOA offers protection. The distribution of bone in the femoral neck was compared in cases of coxarthrosis and postmortem controls to assess the possibility that disease-associated changes might contribute to reduced fragility. Whole cross-section femoral neck biopsies were obtained from 17 patients with cOA and 22 age- and sex-matched cadaveric controls. Densitometry was performed using peripheral quantitated computed tomography (pQCT) and histomorphometry on 10-microm plastic-embedded sections. Cortical bone mass was not different between cases and controls (P > 0.23), but cancellous bone mass was increased by 75% in cOA (P = 0.014) and histomorphometric cancellous bone area by 71% (P < 0.0001). This was principally the result of an increase of apparent density (mass/vol) of cancellous bone (+45%, P = 0.001). Whereas cortical porosity was increased in the cases (P < 0.0001), trabecular width was also increased overall in the cases by 52% (P < 0.001), as was cancellous connectivity measured by strut analysis (P < 0.01). Where osteophytic bone was present (n = 9) there was a positive relationship between the amount of osteophyte and the percentage of cancellous area (P < 0.05). Since cancellous bone buttresses and stiffens the cortex so reducing the risk of buckling, the increased cancellous bone mass and connectivity seen in cases of cOA probably explain, at least in part, the ability of patients with cOA to resist intracapsular fracture of the femoral neck during a fall.     

Trabecular bone remodeling and balance in primary hyperparathyroidism

The total remodeling sequences in 19 primary hyperparathyroid patients and 16 approximately age-matched and sex-matched controls were reconstructed from histomorphometric analyses of bone specimens obtained after intravital tetracycline double labeling. In the primary hyperparathyroid group the total amount of work performed by resorptive cells was reduced, as indicated by the significantly lower three-dimensional mononuclear and preosteoblast-like cell resorption depths (35.8 microns vs 44.5 microns in normals, P less than 0.01 and 45.3 microns vs 56.6 microns in normals, P less than 0.01, respectively). The active resorption period (i.e., the function period for osteoclasts and mononuclear cells) was reduced to 19 days compared to 29 days in normals (P less than 0.05), but no difference with respect to bone resorption rates could be demonstrated between the two groups. The median bone formation period (Sigmaf) in primary hyperparathyroid patients was not different from the value obtained in normals (172 days vs 134 days, respectively), and the matrix appositional rate (Ama), as well as the mineralization lag time (tm), were also unchanged. The initial mineralization rate (Ami(i)) was not significantly different from the value obtained in normals, but averaged over the total bone formation period, a reduced mineralization rate could be demonstrated (0.32 micron3/micron2 per day vs 0.46 micron3/micron2 per day in normals, P less than 0.01). The measured final three-dimensional thickness of bone formed during Sigmaf (mcwTm) was reduced in the primary hyperparathyroid group (51.1 microns vs 55.9 microns in normals, P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanical consequences of bone loss in cancellous bone.

The skeleton is continuously being renewed in the bone remodeling process. This prevents accumulation of damage and adapts the architecture to external loads. A side effect is a gradual decrease of bone mass, strength, and stiffness with age. We investigated the effects of bone loss on the load distribution and mechanical properties of cancellous bone using three-dimensional (3D) computer models. Several bone loss scenarios were simulated. Bone matrix was removed at locations of high strain, of low strain, and random throughout the architecture. Furthermore, resorption cavities and thinning of trabeculae were simulated. Removal of 7% of the bone mass at highly strained locations had deleterious effects on the mechanical properties, while up to 50% of the bone volume could be removed at locations of low strain. Thus, if remodeling would be initiated only at highly strained locations, where repair is likely needed, cancellous bone would be continuously at risk of fracture. Thinning of trabeculae resulted in relatively small decreases in stiffness; the same bone loss caused by resorption cavities caused large decreases in stiffness and high strain peaks at the bottom of the cavities. This explains that a reduction in the number and size of resorption cavities in antiresorptive drug treatment can result in large reductions in fracture risk, with small increases in bone mass. Strains in trabeculae surrounding a cavity increased by up to 1,000 microstrains, which could lead to bone apposition. These results give insight in the mechanical effects of bone remodeling and resorption at trabecular level.     

Effects of h-PTH on cancellous bone mass, connectivity, and bone strength in ovariectomized rats with and without sciatic-neurectomy.

The purpose of this study was to determine whether h-PTH (1-34) treatment would recover cancellous bone connectivity and bone strength in ovariectomized (OVX) or ovariectomized and sciatic-neurectomized (OVX+NX) rats. Seven-month-old female Wistar rats were treated with h-PTH or vehicle (6.0 microg/kg, six times a week, subcutaneously) for four weeks beginning 4, 8, or 12 weeks after OVX or OVX+NX. These were compared to age-matched baseline and sham-operated groups. Right tibiae were used for bone histomorphometry and node-strut analysis, and left tibiae were used for mechanical testing. The bone formation rates in the OVX and OVX+NX rats treated with h-PTH were significantly higher than those in their baseline controls. h-PTH treatment increased the node numbers and failure energies in the OVX rats, compared to their baseline controls, at all time points. However, in the OVX+NX rats, the effects of h-PTH treatment on the node number and failure energy were observed only at four weeks after surgery, but not at eight weeks or 12 weeks after surgery. These results suggest that the lowest limit, at which trabecular connectivity and bone strength are able to be restored by h-PTH, occurred between four and eight weeks in OVX+NX rats, but not in OVX rats. h-PTH cannot recover trabecular connectivity and bone strength in advanced osteopenia.     

Quantitative histological measurements of bone turnover in primary hyperparathyroidism

Undecalcified tetracycline labeled rib biopsies of 7 patients with clinical primary hyperparathyroidism and proven adenoma of the parathyroid glands were examined histologically to study the bone remodeling effects of parathyroid hormone. Unexpectedly wide variations of the static and dynamic bone remodeling data in this group of clinically similar patients was found. Explanations for this conduct still remain highly speculative.     

Biochemical variables associated with bone density in patients with primary hyperparathyroidism.

OBJECTIVE--To clarify the association between primary hyperparathyroidism and cortical osteopenia. DESIGN--Open study. SETTING--Department of Surgery, University of Lund, Sweden. SUBJECTS--38 patients with primary hyperparathyroidism. OUTCOME MEASURES--Correlation between bone density (measured by single photon absorption) and age; sex; serum concentrations of parathyroid hormone and ionised calcium; serum alkaline phosphatase activity; and serum concentration of calcium, phosphate, creatinine, urea, osteocalcin, 25 hydroxycholecalciferol, and 1,25 dihydroxycholecalciferol. RESULTS--There was no difference in bone density between men and women. There was no correlation between bone density and severity of hypercalcaemia or age. No biochemical abnormality was peculiar to the seven patients whose bone density was more than two SD below the population mean. Serum concentrations of 1,25 dihydroxycholecalciferol and osteocalcin both correlated significantly with bone density (p < 0.05) and there was a strong correlation between serum osteocalcin and serum intact parathyroid hormone (p < 0.001). Serum osteocalcin had the strongest correlation with bone density of any of the biochemical variables. CONCLUSION--There is little association between bone density and serum concentration of parathyroid hormone.     

Comparison of roentgenological and histological features of bone changes in primary hyperparathyroidism.

Fifteen cases of bone disease in primary hyperparathyroidism were investigated by comparing X-ray findings with metabolic data and histological features. Besides the usual features of subperiosteal resorption, diffuse demineralization and localized destruction, the less common features of osteosclerosis, and the infrequently described response of the growth plate were also demonstrated. The bone changes in roentgenographs were graded on a five point scale, 0-IV. All cases in Grade IV had parathyroid cancers and extremely high serum and urinary calcium values.     

Anisotropy of osteoporotic cancellous bone.

To investigate the mechanism underlying femoral neck fracture, it is necessary to determine the various mechanical properties, including the bone strength, of the primary compressive group. We investigated the mechanical anisotrophy of the primary compressive group by comparing differences in its mechanical properties, depending on the loading direction. Twenty-three femoral heads of 20 female and 3 male patients with femoral neck fracture were studied. The mean age of these patients was 79.9 years (range, 63-98 years). A total of 82 cubic specimens (6.5 mm in length) were obtained (one to six specimens from each femoral head). The specimens obtained from each femoral head were randomly assigned into two groups: parallel and perpendicular. The parallel group included 43 specimens, and the perpendicular group included 39 specimens. A compressive load was applied either parallel or perpendicular to the primary compressive group of the specimens in each respective group. Three parameters were obtained: compressive stiffness, maximum stress, and maximum energy. We calculated the regression of three parameters against the square of the apparent dry density. These mechanical properties were compared between the two groups by testing the difference of the slopes in two regression lines by using analyses of covariance, in which two main effects of group (nominal value) and the square of the apparent dry density (continuous value) and an interaction between two factors were modeled. Three parameters were significantly correlated with the square of the apparent dry density in both groups. In all three measurements, the difference of the slopes between two regression lines was significantly different. This means that all three measurements decreased in the parallel group more than in the perpendicular one, as apparent dry density decreased. We consider that the bone strength of the proximal femur decreases more when stress is applied in the longitudinal direction (as in walking) and less when stress is applied in the transverse direction (as in a fall) when bone density decreases.