1-α-Hydroxyvitamin D3 treatment decreases bone turnover and modulates calcium-regulating hormones in early postmenopausal women

Chen, J.-T.; Shiraki, Masataka; Hasumi, Katsuhiko; Tanaka, Nahoko; Katase, K.; Kato, Tomoyasu; Hirai, Yasuo; Nakamura, Toshio; Ogata, Etsuro

doi:10.1016/s8756-3282(97)00054-9

Cited by 41 publications

(12 citation statements)

References 33 publications

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“…For this mechanism, there was no significant difference in the level of PTH between the vehicle-treated and zonisamide-treated group, suggesting that bone loss induced by zonisamide was not mediated by the secretion of PTH. It is certain that alfacalcidol has the capacity of inhibiting bone resorption (14,15). Chronic treatment of phenytoin significantly decreased the OC levels, while the serum PYD levels were not affected (1).…”

Section: Discussionmentioning

confidence: 99%

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Effects of Chronic Administration of Zonisamide, an Antiepileptic Drug, on Bone Mineral Density and Their Prevention With Alfacalcidol in Growing Rats

et al. 2003

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Abstract. We investigated the effects of chronic administration of zonisamide, an antiepileptic agent, on bone metabolism in growing rats. Administration of zonisamide at a dose of 80 mg / kg per day, s.c. for 5 weeks significantly decreased bone mineral density (BMD) at the tibial metaphysis and the diaphysis. The percent rate of decrease in BMD at the tibial metaphysis and the tibial diaphysis was 9.2% and 5.0%, respectively. There was no significant difference between these groups in the growth of the rats. Treatment with zonisamide at a dose of 80 mg / kg increased serum pyridinoline level, a marker of bone resorption, while it does not affect the serum intact osteocalcin level, a marker of bone formation. Combined administration of alfacalcidol, an active vitamin D 3 metabolite, at a dose of 0.1 mg / kg per day with zonisamide prevented a decrease in BMD and showed an increase of serum pyridinoline levels. These results suggest that zonisamide may cause bone loss by accelerating bone resorption rather than inhibiting bone formation. Moreover, the bone loss induced by zonisamide could be prevented by combining zonisamide with alfacalcidol.

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Section: Discussionmentioning

confidence: 99%

“…This finding indicates that long-term phenytoin exposure may inhibit bone formation which, at least in part, contributed to bone loss in rats. It is also certain that alfacalcidol has the capacity of accelerating bone formation (14,15).…”

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Administration of Zonisamide, an Antiepileptic Drug, on Bone Mineral Density and Their Prevention With Alfacalcidol in Growing Rats

et al. 2003

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“…Accordingly, in each study, therapy with low doses of calcitriol or alfacalcidol rapidly and markedly stimulate Ca absorption, and the response is dose dependent [87]. This subsequently leads to rapid suppression of PTH secretion and a decrease in bone turnover [87][88][89][90]. Additionally, it appears that the active analog therapy may correct mild osteomalacia associated with aging-associated vitamin D deficiency and may promote micro-callus formation and bone fracture healing.…”

Section: Active Vitamin D Analog (D-hormone) Therapymentioning

confidence: 99%

Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy Versus Active Vitamin D Analog (D-Hormone) Therapy

Lau

Baylink

1999

Calcif Tissue Int

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Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. Secondary hyperparathyroidism due to poor intestinal Ca absorption has been implicated not only in senile osteoporosis but also in age-related bone loss. Accordingly, in population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward, which constitutes a maximum increase at 80 years of age of 50% of the basal value seen at 30 years of age. The cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency. There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)(2)D(3) resulting from decreased renal production of 1,25(OH)(2)D(3); and (3) resistance to 1,25(OH)(2)D(3) action owing to decreased responsiveness to 1, 25(OH)(2)D(3) of target tissues. The cause for the resistance to 1, 25(OH)(2)D(3) could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and senile osteoporosis. There are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)(2)D(3) deficiency/resistance requires active vitamin D analog therapy [1, 25(OH)(2)D(3) or 1alpha(OH)D(3)] to correct the high serum PTH and the Ca malabsorption. In addition, in the elderly, there are patients with decreased intestinal Ca absorption but with apparently normal vitamin D metabolism. Although the cause of poor intestinal Ca absorption in these patients is unclear, these patients, as well as all other patients with secondary hyperparathyroidism (not due to decreased renal function), show a decrease in serum PTH and an increase in Ca absorption in response to therapy with 1, 25(OH)(2)D(3) or 1alpha(OH)D(3). In short, it is clear that some form of vitamin D therapy, either plain vitamin D or 1,25(OH)(2)D(3) or 1alpha(OH)D(3), can be used to correct all types of age-dependent impairments in intestinal Ca absorption and secondary hyperparathyroidism during aging. However, from a clinical standpoint, it is important to recognize the type of vitamin D deficiency in patients with senile osteoporosis so that primary vitamin...

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“…(14,15) Similarly in clinical studies, skeletal efficacy was demonstrated for vitamin D analogues, including reduction of nonvertebral fractures, (5)(6)(7) but the realization of bone efficacy in the absence of hypercalcemia or hypercalciuria has been difficult to achieve. (6)(7)(8)(9)(10)33) We hypothesized that nonsecosteroidal vitamin D receptor ligands could be synthesized to preferentially modulate skeletal efficacy over hypercalcemic effects in vivo. Additionally, we hypothesized that a synthetic compound could have other potential benefits to the elderly, such as improved neuromuscular function, anti-inflammatory/immunomodulation properties, inproved skin quality, and prevention of breast, colon, and prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…(5)(6)(7)(8) However, vitamin D analogues were shown to dose-dependently elevate calcium in sera and in urine, leading to concerns about hypercalcemia and hypercalciuria in humans (5,6,(9)(10)(11)(12)(13) and in animals. (14)(15)(16)(17)(18) ORIGINAL ARTICLE…”

Section: Introductionmentioning

confidence: 99%

A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia

Sato

Iturria

et al. 2010

Journal of Bone and Mineral Research

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Vitamin D 3 analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC 50 ¼ 7.1 AE 1.6 nM) and induced osteocalcin promoter activity (EC 50 ¼ 1.9 AE 1.6 nM). VDRM2 was less potent in inducing Ca 2þ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC 50 ¼ 37 AE 12 nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08 mg/kg per day. Hypercalcemia was observed at a dose of 4.6 mg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35-91]. 1a,25-dihydroxyvitamin D 3 [1a,25(OH) 2 D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046 mg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23 mg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1-13, 3.2-7.7, and 3.5-6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal boneformation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. ß

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1-α-Hydroxyvitamin D3 treatment decreases bone turnover and modulates calcium-regulating hormones in early postmenopausal women

Cited by 41 publications

References 33 publications

Effects of Chronic Administration of Zonisamide, an Antiepileptic Drug, on Bone Mineral Density and Their Prevention With Alfacalcidol in Growing Rats

Effects of Chronic Administration of Zonisamide, an Antiepileptic Drug, on Bone Mineral Density and Their Prevention With Alfacalcidol in Growing Rats

Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy Versus Active Vitamin D Analog (D-Hormone) Therapy

A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia

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