Analgesic Effects of 1st Generation Anti-histamines in Mice.

Pain is sensed, transmitted, and modified by a variety of mediators and receptors. Histamine is a well-known mediator of pain. In addition to their anti-histaminic effects, the classical, or 1st generation, anti-histamines (1st AHs) possess, to various degrees, anti-muscarinic, anti-serotonergic, anti-adrenergic, and other pharmacologic effects. Although there have been attempts to use 1st AHs as analgesics and/or analgesic adjuvants, the advent of non-steroidal anti-inflammatory drugs (NSAIDs) discouraged such trials. We previously reported that in patients with temporomandibular disorders, osteoporosis, and/or osteoarthritis, the analgesic effects of certain 1st AHs (chlorpheniramine and diphenhydramine) are superior to those of the NSAIDs flurbiprofen and indomethacin. Here, we compared analgesic effects among 1st AHs and NSAIDs against responses shown by mice to intraperitoneally injected 0.7% acetic acid. Since 1st AHs are water soluble, we selected water-soluble NSAIDs. For direct comparison, drugs were intravenously injected 30 min before the above tests. Histamine-H1-receptor-deficient (H1R-KO) mice were used for evaluating H1-receptor-independent effects. The tested 1st AHs (especially cyproheptadine) displayed or tended to display analgesic effects comparable to those of NSAIDs in normal and H1R-KO mice. Our data suggest that the anti-serotonergic and/or anti-adrenergic effects of 1st AHs make important contributions to their analgesic effects. Moreover, combination of a 1st AH with an NSAID (cyclooxygenase-1 inhibitor) produced remarkably potent analgesic effects. We propose that a 1st AH, by itself or in combination with a cyclooxygenase-1 inhibitor, should undergo testing to evaluate its usefulness in analgesia.

Once-Weekly Injection of Low-Dose Teriparatide (28.2 µg) Reduced the Risk of Vertebral Fracture in Patients with Primary Osteoporosis.

We conducted a randomized, double-blind trial to assess the effect of 28.2 µg teriparatide versus placebo (1.4 µg teriparatide) on reduction of the incidence of vertebral fractures. Individuals enrolled in this study included patients with primary osteoporosis with one to five vertebral fractures and capable of self-supported walking. Attention was focused on incident vertebral fractures, change in bone mineral density (BMD) of the lumbar spine, and safety. A total of 316 subjects participated in the study, which lasted up to 131 weeks. Incident vertebral fractures occurred in 3.3% of subjects in the 28.2 µg teriparatide-treated group and 12.6% of subjects in the placebo group during the 78-weeks study period. Kaplan-Meier estimates of risk after 78 weeks were 7.5 and 22.2 % in the teriparatide and placebo groups, respectively, with a relative risk reduction of 66.4% by teriparatide (P = 0.008). Lumbar BMD in the 28.2 µg teriparatide group increased significantly by 4.4 ± 4.7 % at 78 weeks, which was significantly higher than the corresponding data in the placebo group (P = 0.001). Adverse events were observed in 86.7% of individuals in the teriparatide group and 86.1% of those in the placebo group. In conclusion, weekly injection of a low-dose of teriparatide (28.2 µg) reduced the risk of incident vertebral fractures and increased lumbar BMD.

Prompt analgesic effect of antihistaminic diphenhydramine ointment on bone-joint-muscle pain as assessed by skin impedance.

Pain is sensed, transmitted, and modified via a variety of mediators and their receptors. Histamine is a well-known mediator of pain. In addition to their antagonistic effects against histamine, classical antihistaminics possess, to various degrees, antimuscarinergic, antiserotonergic, antiadrenergic, local anesthetic, membrane-stabilizing and other pharmacologic actions. Although there have been many attempts to use classical antihistaminics as analgesics and/or analgesic adjuvants, the appearance of non-steroidal anti-inflammatory drugs discouraged such efforts. Here, we compared the analgesic effect of an ointment containing 1% diphenhydramine (a typical first-generation antihistaminic drug) with that of indomethacin (a typical non-steroidal anti-inflammatory drug) in elderly patients with osteoarthritis and/or osteoporosis who complained of bone-joint-muscle pain. Analgesic effects were evaluated by measuring skin impedance and by subjective pain assessments (using a visual recording system) before and after ointment application. Diphenhydramine ointment exerted a prompt and marked analgesic effect that lasted for several hours, as assessed by either skin impedance or subjective pain evaluation. In contrast, the analgesic effect of indomethacin ointment was marginal, and significant only an hour or more later than that of diphenhydramine. These results suggest that diphenhydramine ointment may be useful for the relief of the bone-joint-muscle pains that are common in elderly subjects.

Comparison of the effects of elcatonin and risedronate on back and knee pain by electroalgometry using fall of skin impedance and quality of life assessment using SF-36.

Back and knee pain is a widespread health problem and a serious threat to the quality of life (QOL) in middle-aged and older adults, as it frequently accompanies osteoporosis and osteoarthritis. In order to compare the effects of elcatonin and risedronate on such pain, 20 units of elcatonin was intramuscularly injected to 18 patients, and 5 mg of risedronate was orally administered daily to 20 others with similar backgrounds. Exercise-induced pain was analyzed by measuring the fall of skin impedance by electroalgometry (EAM), and subjective pain was recorded by a visual rating system (VRS) on a scale of 0 (no pain) to 100 (unbearable pain). In patients treated with elcatonin, the mean EAM-estimated pain was significantly reduced after 4, 5 and 6 months of treatment, and the VRS score after 3, 5 and 6 months, indicating a significant analgesic effect. In the risedronate group, however, improvement was less remarkable. Two-way analysis of variance using pain as a dependent variable and treatment group and time as independent variables revealed a significantly greater effect of elcatonin over risedronate on both the EAM and VRS scores, and the influence of treatment time on pain was indistinguishable between the two treatment groups. Effect of exercise load on pain was less on knee load than knee and spine load and spine load, but indistinguishable between the two groups. Changes in QOL were evaluated by the SF-36 system. Norm-based scoring showed significant improvements in 3 of 4 categories for elcatonin and in 2 of 4 for risedronate, suggesting comparable effects on the physical aspects of QOL, whereas responses to emotionally and socially directed questions indicated significant improvements in all 4 categories for risedronate, but none for elcatonin, suggesting a more physical than emotional component in elcatonin effects compared to risedronate.

Analgesic effect of raloxifene on back and knee pain in postmenopausal women with osteoporosis and/or osteoarthritis.

To assess the effect of raloxifene on bone and joint pain, 24 postmenopausal women with back or knee pain or both were randomly divided into two groups, based on the chronological sequence of consultation, to be treated with 60 mg raloxifene and 1 microg alfacalcidol (RA)/day (group RA) or 1 microg alfacalcidol alone (A)/day (group A), respectively, for 6 months. Pain following knee loading (KL) by standing up from a chair and bending the knee by squatting, knee and spine loading (KSL) by walking horizontally and ascending and descending stairs, and spine loading (SL) by lying down supine on a bed and leaving the bed to stand was evaluated by electroalgometry (EAM), based on measurement of the fall of skin impedance, and a visual rating scale (VRS), recording subjective pain on a scale of 0-100 between no pain and unbearable pain. The two groups showed no significant difference as to age, indices of mineral metabolism, back and knee pain, and bone status. RA gave a significantly greater analgesic effect than A by both EAM (P = 0.0158) and VRS (P = 0.0268) on overall comparison of the mean response to all modalities of exercise loading. Paired comparison between pretreatment and posttreatment indicated a significant effect of RA by both EAM (P = 0.0045) and VRS (P = 0.0017), but not that of A. The analgesic effect was more clearly noted on combined knee-spine loading (KSL) and spine loading (SL) than simple knee loading (KL). Monthly comparison of the analgesic effect indicated a significantly better analgesic effect in the fifth month by VRS. RA effect greater than A was more evident by EAM than VRS and during months 3-6 than during 1-2 months, suggesting a slowly progressive effect of RA. Pain evaluation by EAM and VRS mostly gave parallel results, except for a few occasions such as knee loading and spine loading by sitting up and leaving a bed, when EAM detected a positive effect but VRS failed to do so. RA appeared to be more effective on bone and joint pain than A in postmenopausal women according to both EAM and VRS measurements.

[ Nail calcium content in relation to age and bone mineral density].

The growth of nails, and their matrix components, are influenced by several physiological, pathological and environmental factors. Because of the slow rate of nail growth, the elemental composition of the nail is also expected to be affected by transient factors controlling serum components. The mineral components of nail clippings may therefore reflect the long-term patterns of mineral metabolism, such as the rise of creatinine concentration seen in nails in patients with renal failure with hypercreatinemia. Fingernail and toenail Ca concentrations decreased with age in both men and women, whereas Mg concentrations tended to increase. Postmenopausal women had lower finger nail Ca concentrations than premenopausal women. LBMD showed a significant positive correlation with finger nail Ca content. The measurement of finger nail Ca content may be useful as a predictor of osteoporosis.

[Bone and bone related biochemical examinations. Significance of measurement of serum calcium, phosphorus, alkaline phosphatase, corrected calcium and urine calcium].

Classical clinical calcium endocrinology was built on measurements of serum Ca, P and alkaline phosphatase as well as urinary Ca. Serum Ca, the most strictly maintained biological constant, occupies the central role among them, controlling PTH secretion and bone metabolism. Ca is strongly bound to proteins especially albumin, so that total serum Ca values are sometimes misleading, necessitating the use of corrected or ionized Ca. Serum Pi rises early in renal insufficiency, playing an important role in vascular calcification. Growth hormone and thyroid hormone functions are also reflected on serum P. Serum alkaline phosphatase especially the bone-specific type is also important for the evaluation of bone dynamics such as growth and tumor metastasis. These classical datasets should be reevaluated in the light of actions of new compounds such as calcimimetics, P-binders, bisphosphonates, vitamin D derivatives, cytokines, etc.

[Homeostasis and magnesium--comparison with calcium].

Although Mg and Ca, bivalent cations commonly coexisting in nature and living organism, share some similar chemical properties, the role played by Mg in biological regulation and signal transduction is far less important than that by Ca. In contrast to the vast extra- and intra-cellular concentration gradient of Ca as high as 10,000, intracellular Mg is only 3 times as high as extracellular Mg. Systemic Mg metabolism including serum Mg only controlled by renal tubular reabsorption is not as precisely regulated as the Ca counterpart most precisely controlled by parathyroid hormone (PTH), 1,25 (OH)(2) vitamin D and bone. Such difference between Mg and Ca is probably based on the properties of these two kinds of atoms. Mg has a smaller ionic radius with electron arrangement making protein binding more difficult and velocity constant for water binding smaller. Signal transduction by Mg is thus destined to be much less efficient than that by Ca.

[Active absorbable algal calcium (AAACa) changes calcium paradigm].

Active Absorbable Algal Calcium (AAA Ca) is made by submaximally (800 degrees ) heating cleaned oyster shell under reduced pressure and mixing it with similarly heated seaweed (Cystophyllum fusiforme). AAA Ca, the best absorbed from the intestine than other available calcium compounds, consequently most efficiently suppresses parathyroid hormone secretion, increases bone mineral density and decreases vertebral fracture. Aging is associated with calcium deficiency, mostly because of the decreased biosynthesis of 1,25 (OH)2 vitamin D in the kidney. Parathyroid hormone consequently increases, contributing to various diseases associated with aging such as osteoporosis or decrease of calcium in the bone, as well as hypertension, arteriosclerosis, Alzheimer's disease and osteoarthritis due to paradoxical increase of calcium in vascular walls, brain, cartilage and intracellular compartment of many kinds of cells. Mild calcium deficiency is hard to detect despite these serious consequences because of the remarkable constancy of blood calcium concentration maintained by elaborate homeostatic control. Only by successfully counteracting calcium deficiency by AAA Ca with outstanding absorbability, the phenomenon of calcium paradox becomes a recognizable reality within our reach.

[Alzheimer disease and calcium].

Calcium deficiency due to insufficient nutritional intake, poor intestinal absorption or excessive urinary loss leading to secondary hyperparathyroidism, increase of calcium influx into nerve cells causing cell death may lead to neuronal dysfunction and cell death as in dialysis encephalopathy with EEG changes and decrease of nerve conduction velocity in chronic renal failure and Alzheimer's disease in aging. Intracellular free calcium (Ca i) is increased in nerve cells showing neurofibrillar tangles associated with tau protein in Alzheimer's disease. Increase of Ca i facilitates presenilin mutation with consequent augmentation of short chain amyloid beta production which further increase Ca i. Peroxide radical production by amyloid beta and metals such as Fe, Cu and Mn is prompted by an increase of Ca i. Plasma membrane damage caused by lipid peroxidation further increases Ca i. Neurotoxic action of apolipoprotein E(4) increasing the risk for Alzheimer's disease may be explained by lipid peroxidation and rise of Ca i. Beneficial effect of estrogen in preventing Alzheimer's disease may also be explained by its anti-oxidant effect and stimulation of intestinal calcium absorption. By increasing calcium intake and administration of active form of vitamin D which cannot be sufficiently supplied by the aging kidney, one step forward should be made in the prevention and treatment of Alzheimer's disease.

[Mechanism of intracerebral calcification in hypoparathyroidism].

The mechanism of intracranial calcification in hypoparathyroidism, more frequently seen in pseudo--than idiopathic hypoparathyroidism, has not been completely elucidated, but may be related more to the duration of hypocalcaemia and hyperphosphatemia than parathyroid hormone itself. Hyperphosphatemia promotes ectopic calcification, especially in blood vessel and periarticular tissue in renal failure, but in brain tissue in hypoparathyroidism. Participation of PTH receptor2 in the brain and superoxide production by mitochondria in hypoparathyroidism should be explored with reference to intracerebral calcification and neurodegenerative diseases.

Assessment of alveolar bone mineral density as a predictor of lumbar fracture probability.

INTRODUCTION: Osteoporosis and tooth loss have been linked with advancing age, but no clear relationship between these conditions has been proven. Several studies of bone mineral density measurements of the jaw and spine have shown similarities in their rate of age-related deterioration. Thus, measurements of jawbone density may predict lumbar vertebral bone density. Using jawbone density as a proxy marker would circumvent the need for lumbar bone measurements and facilitate prediction of osteoporotic spinal fracture susceptibility at dental clinics. We aimed to characterize the correlation between bone density in the jaw and spine and the incidence of osteoporotic spinal fractures. METHODS: We used computerized radiogrammetry to measure alveolar bone mineral density (al-BMD) and dual-energy X-ray absorptiometry to measure lumbar bone mineral density (L-BMD). L-BMD and al-BMD in 30 female patients (average age: 59 ± 5 years) were correlated with various patient attributes. Statistical analysis included area under the curve (AUC) and probability of asymptomatic significance (PAS) in a receiver operating characteristic curve. The predictive strength of L-BMD T-scores (L-BMD[T]) and al-BMD measurements for fracture occurrence was then compared using multivariate analysis with category weight scoring. RESULTS: L-BMD and al-BMD were significantly correlated with age, years since menopause, and alveolar bone thickness. Both were also negatively correlated with fracture incidence. Category weight scores were -0.275 for a L-BMD(T) <80%; +0.183 for a L-BMD(T) ≥ 80%; -0.860 for al-BMD <84.9 (brightness); and +0.860 for al-BMD ≥ 84.9. AUC and PAS analyses suggested that al-BMD had a higher association with fracture occurrence than L-BMD. CONCLUSIONS: Our results suggest the possible association between al-BMD and vertebral fracture risk. Assessment of alveolar bone density may be useful in patients receiving routine dental exams to monitor the clinical picture and the potential course of osteoporosis in patients who may be at a higher risk of developing osteoporosis.

Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk.

CONTEXT: Weekly teriparatide injection at a dose of 56.5 µg has been shown to increase bone mineral density. OBJECTIVE: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. DESIGN AND SETTING: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. PATIENTS: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. INTERVENTION: Subjects were randomly assigned to receive once-weekly s.c. injections of teriparatide (56.5 µg) or placebo for 72 wk. MAIN OUTCOME MEASURE: The primary endpoint was the incidence of new vertebral fracture. RESULTS: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. CONCLUSION: Weekly s.c. administration of teriparatide at a dose of 56.5 µg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk.

Fractional absorption of active absorbable algal calcium (AAACa) and calcium carbonate measured by a dual stable-isotope method.

With the use of stable isotopes, this study aimed to compare the bioavailability of active absorbable algal calcium (AAACa), obtained from oyster shell powder heated to a high temperature, with an additional heated seaweed component (Heated Algal Ingredient, HAI), with that of calcium carbonate. In 10 postmenopausal women volunteers aged 59 to 77 years (mean ± S.D., 67 ± 5.3), the fractional calcium absorption of AAACa and CaCO(3) was measured by a dual stable isotope method. (44)Ca-enriched CaCO(3) and AAACa were administered in all subjects one month apart. After a fixed-menu breakfast and pre-test urine collection (Urine 0), (42)Ca-enriched CaCl(2) was intravenously injected, followed by oral administration of (44)Ca-enriched CaCO(3) without carrier 15 minutes later, and complete urine collection for the next 24 hours (Urine 24). The fractional calcium absorption was calculated as the ratio of Augmentation of (44)Ca from Urine 0 to Urine 24/ augmentation of (42)Ca from Urine 0 to Urine 24. Differences and changes of (44)Ca and (42)Ca were corrected by comparing each with (43)Ca. Fractional absorption of AAACa (mean ± S.D., 23.1 ± 6.4), was distinctly and significantly higher than that of CaCO(3 )(14.7 ± 6.4; p = 0.0060 by paired t-test). The mean fractional absorption was approximately 1.57-times higher for AAACa than for CaCO(3). The serum 25(OH) vitamin D level was low (mean ± S.D., 14.2 ± 4.95 ng/ml), as is common in this age group in Japan. Among the parameters of the bone and mineral metabolism measured, none displayed a significant correlation with the fractional absorption of CaCO(3) and AAACa. Higher fractional absorption of AAACa compared with CaCO(3) supports previous reports on the more beneficial effect of AAACa than CaCO(3) for osteoporosis.

Comparison of the analgesic effects of bisphosphonates: etidronate, alendronate and risedronate by electroalgometry utilizing the fall of skin impedance.

Analgesic effects of etidronate, alendronate and risedronate were compared in patients with osteoporosis and/or osteoarthritis by measuring the fall of skin impedance along with conventional subjective pain-estimation by visual rating scale (VRS). One hundred ninety-nine postmenopausal women consulting the Osteoporosis and Osteoarthritis Clinic of Katsuragi Hospital complaining of back and/or knee pain were randomly divided into four groups; Group A (49 subjects) given 5 mg/day alendronate, Group E (50 subjects) 200 mg/day etidronate, Group R (50 subjects) 2.5 mg/day risedronate and Group P no bisphosphonate. None of the four groups showed significant deviation from others as to age and parameters of bone metabolism. Proportions of subjects with osteoporosis was 18-40%. Those with osteoarthritis of the spine and knee, higher than Grade II according to the Nathan and Lawrence-Kellgren scale, respectively, was 45 and 61%, respectively, without a significant difference among the four groups. Significant positive correlation was found between the fall of skin impedance and pain expressed in VRS. Attenuation of exercise-induced fall of skin impedance and also subjective pain expressed in VRS was greatest in Group E with a highly significant difference from Groups A (P = 0.0002 and P < 0.0001), R (P < 0.0001 and P = 0.0014) and P (P < 0.0001 and P < 0.0001). Neither A nor R showed significant difference from P as to the fall of skin impedance. Among the three bisphosphonates tested, etidronate appeared to be outstanding in analgesic effects.

Postural stabilizing effect of alfacalcidol and active absorbable algal calcium (AAA Ca) compared with calcium carbonate assessed by computerized posturography.

Sway and postural instability have drawn attention as a risk factor for osteoporotic fracture, in addition to low bone mineral density (BMD) and poor bone quality. In view of the fracture-reducing effect of alfacalcidol and active absorbable algal calcium (AAA Ca) not readily explained by rather mild increases of BMD, attempts were made to evaluate postural stabilizing effect of alfacalcidol, AAA Ca, and calcium carbonate (CaCO(3)) by computerized posturography. Track of the gravity center was analyzed to calculate parameters related to tract length, track range, and track density to express the degree of sway before and after supplementation in 126 subjects ranging in age between 20 and 81 years randomly divided into four groups. Supplementation with AAA Ca containing 900 mg elemental Ca (group A), no calcium (group B), CaCO(3) also containing 900 mg elemental Ca (group C), or alfacalcidol (group D) continued daily for 12 months. For each parameter, the ratio closed eye value/open eye value (Romberg ratio) was calculated to detect aggravation of sway by eye closure. Age, parameters of Ca and P, and proportions of subjects with fracture and those with low BMD showed no marked deviation among the groups. With eyes open, significant decreases of a track range parameter (REC) from group B was noted in groups A (P = 0.0397) and D (P = 0.0296), but not in group C according to multiple comparison by Scheffe, indicating superior postural stabilizing effect of A and D over C. In the first 2 months, a significant fall was already evident in REC from group B in group D (P = 0.0120) with eyes open. Paired comparison of sway parameters before and after supplementation revealed a significant increase of track density parameter (LNGA), indicating sway control efficiency and a significant decrease of REC in groups A and D compared to group B with eyes open. With eyes closed, only group A showed a significant improvement from group B (P = 0.0456; Fig. 1), with a significant shortening on paired After/Before comparison (P = 0.0142; Fig. 2). Computerized posturography appears to be useful in analyzing sway phenomena especially as to the effects of vitamin D and various Ca preparations.

Clinical effect of bisphosphonate and vitamin D on osteoporosis: reappraisal of a multicenter double-blind clinical trial comparing etidronate and alfacalcidol.

As inhibitors of bone resorption, bisphosphonates and vitamin D derivatives have been extensively used for the treatment of osteoporosis in various parts of the world, but the clinical effects of these two groups of agents have rarely been compared in detail. A multicenter, prospective, double-blind controlled study was started comparing the effects of etidronate and alfacalcidol (1-alpha-hydroxycholecalciferol) in 414 patients with established osteoporosis from 36 centers. Among these patients, 135 were given 400 mg etidronate daily at bedtime for 2 weeks followed by 10 weeks off treatment, and this cycle was repeated four times along with a placebo indistinguishable from the alfacalcidol capsule daily throughout the 48 weeks of study (Group A, High Dose Etidronate Group). In 133 patients, 200 mg etidronate was used instead of 400 mg (Group B, Low Dose Etidronate Group). In 138 patients, 1 microg alfacalcidol was given daily throughout the 48-week study period along with a placebo indistinguishable from the etidronate tablet in four separate periods of 2 weeks (Group C, Control Group). Dual-energy X-ray absorptiometry of the lumbar spine (L2-L4) was performed before the beginning of the study and every 12 weeks thereafter. Changes in spinal deformity were also assessed based on the lateral thoracic and lumbar spine X-ray films taken before and after the study. The lumbar spine bone mineral density (BMD) changes were +3.4% +/- 0.6% (mean +/- SEM) in Group A, +2.4% +/- 0.5% in Group B, and -0.5% +/- 0.4% in Group C, the former two being significantly higher than the last. New occurrence of spinal compression fracture was also significantly reduced in Group A compared to Group C. In patients without previous fracture at entry, incident fracture was 10.2% in Group C, but 0% in Groups A and B. In patients with prevalent fracture at entry, corresponding figures were 21.5% (Group C), 12.0% (Group A), and 13.2% (Group B), respectively. Alfacalcidol maintained lumbar spine BMD, preventing a decrease for 48 weeks, and etidronate significantly increased it further, demonstrating its usefulness in the treatment of established osteoporosis.

AlphaVbeta3 integrin ligands enhance volume-sensitive calcium influx in mechanically stretched osteocytes.

We propose that specific osteocyte-matrix interactions regulate the volume-sensitive calcium influx pathway, which we have shown is mediated by stretch-activated cation channels (SA-Cat) and is essential for the stretch-activated anabolic response in bone. The current study measured the hypotonic swelling-induced increase in cytosolic calcium concentration, [Ca(2+)](i), in rat osteocytes, and found that cells adherent to different matrices behave differently. Osteopontin and vitronectin, matrix molecules that bind the alpha(V)beta(3) integrin, induced larger responses to the hypotonic swelling than other matrix molecules that bind other integrins. Addition of echistatin, which is a soluble alpha(V)beta(3) ligand, significantly enhanced the hypotonic [Ca(2+)](i) increase in addition to inducing an immediate increase in [Ca(2+)](i) by itself. These results strongly support the contention that alpha(V)beta(3) integrin signaling in osteocytes interacts with that in mechanotransduction, which is downstream of SA-Cat.

Nail calcium and magnesium content in relation to age and bone mineral density.

In view of the importance of calcium (Ca) and magnesium (Mg) as major bone components and nutrients controlling bone metabolism, and the ready availability of nail samples for analysis, clippings of fingernails and toenails were analyzed for Ca and Mg. The clippings were dissolved in nitric acid and analysis was done, using atomic absorption spectrophotometry, in 169 women and 115 men between 20 and 80 years of age. Fingernail Ca concentration in men decreased from 927 +/- 50 ppm (mean +/- SEM) in their twenties to 464 +/- 50 ppm in their eighties, with a significant negative correlation with age (r = -0.322; P < 0.0001) and such a negative correlation was also shown in the women (r = -0.269; P = 0.0004). Toenail Ca concentrations also decreased significantly with age in men (r = -0.534; P < 0.0001) and women (r = -0.224; P = 0.0016). Fingernail Mg concentration, in contrast, increased significantly with age in both men (r = 0.209; P = 0.0145) and women (r = 0.280; P < 0.0001), but toenail Mg failed to show significant changes with age in either men or women. Multiple stepwise regression analysis of age and lumbar bone mineral density (LBMD) on fingernail Ca concentration eliminated age before LBMD. In a separate group of 33 women in their sixties, a significant positive correlation was noted between fingernail Ca and LBMD (r = 0.544; P = 0.0016) and between toenail Ca and LBMD (r = 0.399; P = 0.0215). A negative correlation was also noted between fingernail Mg concentration and LBMD (r = -0.389; P = 0.0252). Nail mineral content may be utilized as one of the indicators of bone mineral metabolism.