Zhaopo Geng

The Phytoestrogen Genistein Reduces Bone Loss in Short-Term Ovariectomized Rats

Abstract: The incidence of fractures and of osteoporosis differs between Oriental and Western Caucasian women. This may depend, at least in part, on nutritional factors, including dissimilarities in dietary intake of phytoestrogens. To investigate this possibility, 2-month-old female rats were ovariectomized (OVX) or sham-operated (SHAM), fed a casein-based diet, injected daily with subcutaneous genistein (GEN), the most abundant and best characterized phytoestrogen, or vehicle (Veh) and killed 21 days after surgery. As expected, ovariectomy resulted in loss of bone mineral density (BMD) and in uterine atrophy. However, administration of 5 mg GEN per gram body weight (b.w.) ameliorated the ovariectomy-induced loss of BMD (189 ± 2 mg/cm2 in OVX and 192 ± 2 in OVX with 5 mg GEN/g b.w. per day; p<0.05). One microgram GEN per gram body weight did not affect the BMD loss and the effect of the 5 mg and 25 mg GEN per gram body weight were statistically not different. A trend toward reduced uterine atrophy (21% reduction) was noted with the 25 mg GEN dose, but not with the 1 mg and 5 mg doses. A separate experiment with 2 x 2 factorial design was conducted to elucidate the mechanism by which GEN ameliorates ovariectomy-induced bone loss. In this experiment, histomorphometry demonstrated a dramatic reduction in trabecular bone volume after ovariectomy (7.6 ± 0.7% of total bone volume in SHAM-Veh vs 3.3 ± 0.2% in OVX-Veh; p<0.01) and less bone loss in OVX rats injected with 5 mg GEN per gram per day (3.3 ± 0.2% of total bone volume in OVX-Veh vs 5.2 ± 0.4% in OVX-GEN; p<0.01). Administration of GEN was associated with higher bone formation rate per tissue volume and with a trend toward a higher number of osteoblasts per bone perimeter. The parameters of bone resorption were not affected by GEN. The concentration of serum osteocalcin and the urinary excretion of deoxypyridinoline provided corroborating results. Since production of proinflammatory cytokines is intimately involved in the pathogenesis of postmenopausal osteoporosis, the effect of GEN on lipopolysaccharide-induced in vitro production of Tumor necrosis factor-alpha (TNFa) was tested in monocytic cells from the same four rat groups. Production of TNFa was markedly elevated in OVX-Veh as compared with the SHAM-Veh rats, but this was blocked by GEN in the OVX rats. This study shows that GEN reduces both trabecular and compact bone loss after ovariectomy and that this protective effect differs from that of estrogen, since it depends on stimulation of bone formation rather than on suppression of bone resorption. Lack of action of GEN on uterine atrophy supports the possibility that this GEN dose affects target tissues via non-estrogenic mechanisms. Modulation of cytokine production may be involved in the effect of GEN on bone.

Predictive value of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis

With the increasing occurrence of adynamic bone disease, it is essential to determine the level of bone turnover in chronically dialyzed patients before instituting vitamin D therapy. To assess the value of serum parathyroid hormone (PTH) levels for prediction of bone turnover, we determined sensitivity, specificity, and predictive value positive of serum PTH, alone or in combination with other variables, in 79 patients who underwent one or two bone biopsies. Serum PTH levels were determined by a radioimmunometric assay and were obtained at the time of bone biopsies. Patients were classified into (1) low or normal and (2) high bone turnover according to the value of activation frequency of bone. There were 57 biopsy specimens taken from hemodialysis patients and 39 specimens from continuous ambulatory peritoneal dialysis patients (CAPD). All patients with serum PTH levels within or below the normal range had low or normal bone turnover. Values of serum PTH above 450 pg/mL were 100% and 95.5% specific for high bone turnover in hemodialysis and CAPD patients, respectively. Values of serum PTH between 65 and 450 pg/mL had worse predictive value positive in CAPD patients (48.6% to 78.6%) than in hemodialysis patients (67.3% to 87.1%). When other characteristics of the patients were taken into consideration, only age in hemodialysis patients and serum ionized calcium in CAPD patients improved the predictive value of serum PTH. All hemodialysis patients younger than 45 years of age with serum PTH levels above 65 pg/mL (n = 15) had high bone turnover, and CAPD patients with low or normal bone turnover had higher serum ionized calcium. However, overall, bone turnover could not be predicted by serum PTH measurements in 30% of hemodialysis and 51.3% of CAPD patients. The data suggest that for patients with serum PTH levels between 65 and 450 pg/mL, bone biopsies are indicated to precisely assess bone turnover prior to initiation of vitamin D therapy.

Intermittent and Continuous Administration of the Bisphosphonate Ibandronate in Ovariohysterectomized Beagle Dogs: Effects on Bone Morphometry and Mineral Properties

Bisphosphonates have emerged as a valuable treatment for postmenopausal osteoporosis. Bisphosphonate treatment is usually accompanied by a 3–6% gain in bone mineral density (BMD) during the first year of treatment and by a decrease in bone turnover. Despite low bone turnover, BMD continues to increase slowly beyond the first year of treatment. There is evidence that bisphosphonates not only increase bone volume but also enhance secondary mineralization. The present study was conducted to address this issue and to compare the effects of continuous and intermittent bisphosphonate therapy on static and dynamic parameters of bone structure, formation, and resorption and on mineral properties of bone. Sixty dogs were ovariohysterectomized (OHX) and 10 animals were sham‐operated (Sham). Four months after surgery, OHX dogs were divided in six groups (n = 10 each). They received for 1 year ibandronate daily (5 out of 7 days) at a dose of 0, 0.8, 1.2, 4.1, and 14 μg/kg/day or intermittently (65 μg/kg/day, 2 weeks on, 11 weeks off). Sham dogs received vehicle daily. At month 4, there was a significant decrease in bone volume in OHX animals (p < 0.05). Doses of ibandronate ≥ 4.1 μg/kg/day stopped or completely reversed bone loss. Bone turnover (activation frequency) was significantly depressed in OHX dogs given ibandronate at the dose of 14 μg/kg/day. This was accompanied by significantly higher crystal size, a higher mineral‐to‐matrix ratio, and a more uniformly mineralized bone matrix than in control dogs. This finding lends support to the hypothesis that an increase in secondary mineralization plays a role in gain in BMD associated with bisphosphonate treatment. Moreover, intermittent and continuous therapies had a similar effect on bone volume. However, intermittent therapy was more sparing on bone turnover and bone mineral properties. Intermittent therapy could therefore represent an attractive alternative approach to continuous therapy.

Calcitonin Alters Bone Quality in Beagle Dogs

Because of its antiresorptive properties, calcitonin is widely used to prevent and treat osteoporosis. A stimulatory effect of calcitonin on osteoblasts has also been reported; however, a recent histologic study points to a negative effect of calcitonin on mineralization of cancellous bone. The present experiment was performed to determine whether the observed histological signs of alterations in mineralization are also observed in cortical bone and whether this results in changes in mechanical properties, mineral densities, or mineral properties of canine bone. Sixteen female adult beagle dogs were randomly allocated to receive either human calcitonin at a dose of 0.25 mg/dog (50 IU, n = 8) or vehicle (mannitol, n = 8) every other day for 16 weeks. At the end of the study, the dogs were euthanized. Both tibiae, L1 and L5 vertebrae, and iliac crest bone samples were excised and defleshed. Torsional mechanical properties of tibial diaphyses and compressive strengths of vertebrae were measured. Bone mineral densities (BMD) of tibiae and vertebrae were measured by using dual‐energy X‐ray absorptiometry. Ultrastructural mineral characteristics of iliac crest bone were determined by gravimetry and Fourier transform infrared spectroscopy (FTIR). Bone histomorphometry was performed in the cortical envelope of the iliac crest. Tibiae from dogs treated with calcitonin withstood significantly less maximum torque until failure, required less torsional energy to reach the maximum torque, and had less torsional stiffness than the tibiae from dogs treated with vehicle (p < 0.05). Cancellous cores of vertebrae from calcitonin‐treated dogs withstood less compressive mechanical loading than did vertebral cores from vehicle‐treated animals (p < 0.05). Dogs treated with calcitonin had less BMD of both tibiae and vertebrae than vehicle‐treated animals (p < 0.05). Bones from calcitonin‐treated dogs had significantly less ash content, which correlated with the lower phosphate‐to‐amide I (detected by FTIR) and greater carbonate‐to‐phosphate ratios than did bones from vehicle‐treated dogs (p < 0.05). Calcitonin‐treated dogs exhibited a decrease in bone formation and mineralization rates and an increase in mineralization lag time. These results point to a negative effect of calcitonin on bone quality. These findings are intriguing and call for further studies addressing whether the observed abnormalities are transient or permanent.

Parathyroid hormone/parathyroid hormone-related peptide type 1 receptor in human bone.

The parathyroid hormone/parathyroid hormone‐related peptide (PTH/PTHrP) receptor (denoted as PTH‐1R) is a key signaling factor through which calcium‐regulating hormones PTH and PTHrP exert their effects on bone. There are contradictory reports regarding the capability of osteoclasts to express PTH‐1R. To address this issue in humans, bone biopsy specimen samples from 9 normal controls and 16 patients with moderate to severe secondary renal hyperparathyroid bone disease (2°HPT) with elevated PTH levels were studied to determine whether osteoclasts in the bone microenvironment express PTH‐1R messenger RNA (mRNA) and protein. We report that osteoclasts express the PTH‐1R mRNA but the protein is detected only in patients with 2°HPT. The PTH‐1R mRNA and protein also were found in osteoblasts, osteocytes, and bone marrow cells. Receptor expression was higher in osteoclasts and osteoblasts of patients with 2°HPT than normal controls (98.0 ± 1.1% vs. 65.7 ± 14.3% and 65.8 ± 3.4% vs. 39.1 ± 6.2%; p < 0.01, respectively). Approximately half of osteoclasts found in bone of patients with 2°HPT have the PTH‐1R protein. In patients with 2°HPT, a positive relationship exists between erosion depth, a parameter of osteoclastic activity, and the percentage of osteoclasts with PTH‐1R protein (r = 0.58; p < 0.05). In normal controls, an inverse relationship exists between the percentage of osteoblasts with receptor mRNA, mRNA signals/cell, and serum PTH levels (r = −0.82 and p < 0.05 and r = −0.78 and p < 0.01, respectively). The results provide the novel evidence of PTH‐1R in human osteoclasts and suggest a functional role for the receptors in 2°HPT.

Oncogenic osteomalacia associated with metastatic prostate carcinoma : case report and review of the literature

umor-induced osteomalacia is a disorder of mineralization caused by neoplasm-induced phosT phaturia. Laboratory features include low serum 1,25(OH)’D, hypophosphatemia, and phosphaturia. Although almost exclusively associated with mesenchymal tumors, an association between prostate cancer and osteomalacia has been described in at least six subjects.’,’ These six subjects together with the subject of this report, the oldest reported case, represent approximately 10% of all cases.