- Email: [email protected]
Calcium and vitamin D
I OS
Abstracts
I 29
Bone Vol. 27, No. 4, Supplement October 2000: I SSS4S
130 THE EFFECTS OF STATINS AND RELATED COMPOUNDS ON BONE FORMATION. GR Mundy. Univ. TX Hlth. Sci. Ctr., San Antonio, TX USA 78229-3900. The most compelling need in bone research is an anabolic agent that increases new bone formation, restores bone microarchitecture, is orally bioavailable and has a satisfactory toxicity profile No such agent currently exists. Several agents are currently under investigation including parathyroid hormone, fluoride and vitamin D metabolites. Parathyroid hormone causes substantial increases in trabecular bone but is a peptide. Fluoride is unlikely to become a widely acceptable agent because it stimulates formation of fragile bone. Vitamin D metabolites enjoy widespread use in Japan, but studies in the United States so far have not shown convincing efficacy in patients with osteoporosis. Contmued refinement of these metabolites searching for those with more satisfactory therapeutic profiles continues. Recently, we have evaluated chemical libraries using molecular targets which are specific for bone formation, and in particular transcription of the BMP-2 gene. BMP-2 is an autocrine-paracrine factor in osteoblast differentiation. This makes it unique among the bone growth factors. From a natural products collection, we found that the statins, drugs which inhibit HMG-CoA reductare, the rate-limiting enzyme in the mevalonate pathway. specifically enhanced BMP-2 transcription. These agents cause increases in bone formation in organ cultures of murine calvaria, when appbed locally to periosteal bone surfaces in mice, and when administered systemically to intact and ovariectomized rats. This increase in bone formation was confirmed by increased bone formation rates. There was also reduction in osteoclast numbers. The molecular mechanisms which are responsible for linking HMG-CoA reductase and BMP-2 transcription remain to be elucidated, but preliminary evidence suggests enhanced nitric oxide generatmn in bone cellsis involved. Since current statins are not well distributed to peripheral tissues beyond the liver, their therapeutic efficacy m patients remains to be detenined in randomized control trials. However. observational studies in patients treated with statins for lipid-lowering suggest that there are beneficial effects on subsequent fracture risk.
THERAPEUTIC POTENTIAL OF THE OPG/ODF SYSTEM m R Dunstan, Development, Amgen, Thousand Oaks, California, USA Regulation of bone resorption by homeostatic and pathological stimuli converges on the Osteoprotegerin (OPG), RANK and RANKLIODFI TRANCE/OPGL signaling pathway. RANKL is a cytokine essential for osteoclast differentiation with a role also in osteoclast activation and survival RANK is a TNFR superfamily member and is the signaling receptor for RANKL OPG is a soluble secreted decoy receptor which competes for binding of RANKL and inhibits osteoclast differentiation OPG knockout mice have severe osteoporosis Mice and activation deficient in RANK or RANKL lack osteoclasts and have severe osteopetrosis. RANK knockout mice and mice treated with high doses of OPG. are resistant to the calcemic and resorptive effects of osteotropic hormones and cytokines indicating they require RANKL signaling for their action. It is likely that increased expression of RANKL relative to OPG mediates stimulation of bone resorption b, hormones and inflammatory cytokines. Treatment of healthy postmenopausal women with a modified form of OPG profoundly suppresses levels of urinary N-telopeptide of collagen and other surrogate markers of bone resorption. Mutations in RANK that increase RANK signaling appear to be responsible for familial expansile osteolysis. These results confirm the importance of RANKL in human osteoclast biology. Defects in RANK signaling may be involved in some cases of human osteopetrosis or Pagets disease of bone but this has not yet been confirmed. The essential requirement for RANKL for the activity of osteotropic hormones and cytokines suggests that OPG or other inhibitors of the RANK signaling pathway will be powerful inhibitors of pathological This has been supported by studies showing bone bone resorption protection by OPG in rodent models of hypercalcemia of malignancy, metastatic bone disease, inflammatory joint disease and ovariectomyrelated osteoporosis
131 CALCIIJM AND VITAMIN D P.J. Meunier - Department of Rheumatology and Bone Diseases. INSERM U 403, Edouard Herriot Hospital, Lyon, France. The most important nutrients for bone health are calcium and vitamin D. Calcium (Ca) functions as a threshold nutrient and below some critical value -about 800 mgiday- bone mass will be limited by available Ca supplies, whereas above that threshold no further benefit will accrue from additional increases in intake. More than 80 percent of elderly women have a dietary Ca intake below the recommended intake for postmenopausal women (1200mg/day). Vitamin D is particularly important for adaptation to low Ca intake. Serum 25(OH)D is the best functional indicator of vit.D status which depends on synthesis initiated by solar irradiation of the skin and dietary intake. Severe and long-lasting vit.D deficiency leads to frank osteomalacia. A less severe reduction in s.25(OH)D, named vit.D insnficiency, induces a secondary hyperparathyroidism which accelerates and bone loss, particularly in elderly subjects, Recent studies have shown that the s.2S(OH)D level corresponding to the lower limit of vit.D suf,ciency is much higher than the “classical“ threshold of 30nmol/l (or 12ng/ml). This reappraisal has two practical consequences : vit.D insufficiency, as defined by a s.25(OH)D below 70-8Omnol/l, is much more common than previously believed and this is relevant to larger possibilities of vit.D (or vit. D+Ca) supplements for preventing fractures by minimizing s. parathyroid hormone (PTH). Controlled studies performed in institutionalized elderly women (DECALYOS I and II studies) and in independent elderly subjects have demonstrated a significant protective effect against hip and non vertebral fractures of a combined supplement of Ca and vit.D. It is important to ensure that s.2S(OH)D level obtained after this supplementation reaches the threshold minimizing s.PTH. Correction of Ca and vit.D insufticiency should be the first step of any therapeutic strategy for OP.
132 NEW ESTROGENS. Robert Marcus, M.D. Stanford University Stanford CA USA. Despite enthusiasm for the SERM concept, only two, tamoxifen and raloxifene, now participate in the clinical marketplace. Others, such as droloxifene and idoxifene, were abandoned because of inadequate tissue selectivity (i.e. endometrial hyperplasia). New SERMs continue to undergo development for potential osteoporosis and breast cancer indications. These include Lasofoxifene and TSE-424. Delta 8,9dehydroestrone, a constituent of conjugated equine estrogens, is also tissue-selective and accounts for a non-trivial portion of the total estrogenic activity of this product. Although its effects are interesting, it does not appear destined for development as monotherapy. Current SERMs act as estrogen antagonists in the brain. Beyond implications for hot flashes lies persistent concern about adverse cognitive effects. No compelling data yet satisfy this concern. Tibolone, a complex molecule with estrogenic, androgenic, and progestational actions, Because of its appears close to approval in the United States. progestational effects, endomehial protection is not an issue, but reductions in HDL-cholesterol might be problematic. Phytoestrogens have captured the hearts and minds of many consumers. In high doses ipriflavone is a moderately effective antiresorptive agent. At doses available from health food stores, little if any effect on bone turnover is evident. 1998-9 was not a good time for HRT. Publications related to heart disease, Alzheimer’s disease, and breast cancer all increased public concern about estrogen toxicity. Many patients respond by trying lower doses and alternative products. In the absence of clear evidence that such strategies offer skeletal protection, it may be prudent to place those patients on a bisphosphonate, so that no matter what choices they make re. HRT, their bone will be protected.
Abstracts
I 29
Bone Vol. 27, No. 4, Supplement October 2000: I SSS4S
130 THE EFFECTS OF STATINS AND RELATED COMPOUNDS ON BONE FORMATION. GR Mundy. Univ. TX Hlth. Sci. Ctr., San Antonio, TX USA 78229-3900. The most compelling need in bone research is an anabolic agent that increases new bone formation, restores bone microarchitecture, is orally bioavailable and has a satisfactory toxicity profile No such agent currently exists. Several agents are currently under investigation including parathyroid hormone, fluoride and vitamin D metabolites. Parathyroid hormone causes substantial increases in trabecular bone but is a peptide. Fluoride is unlikely to become a widely acceptable agent because it stimulates formation of fragile bone. Vitamin D metabolites enjoy widespread use in Japan, but studies in the United States so far have not shown convincing efficacy in patients with osteoporosis. Contmued refinement of these metabolites searching for those with more satisfactory therapeutic profiles continues. Recently, we have evaluated chemical libraries using molecular targets which are specific for bone formation, and in particular transcription of the BMP-2 gene. BMP-2 is an autocrine-paracrine factor in osteoblast differentiation. This makes it unique among the bone growth factors. From a natural products collection, we found that the statins, drugs which inhibit HMG-CoA reductare, the rate-limiting enzyme in the mevalonate pathway. specifically enhanced BMP-2 transcription. These agents cause increases in bone formation in organ cultures of murine calvaria, when appbed locally to periosteal bone surfaces in mice, and when administered systemically to intact and ovariectomized rats. This increase in bone formation was confirmed by increased bone formation rates. There was also reduction in osteoclast numbers. The molecular mechanisms which are responsible for linking HMG-CoA reductase and BMP-2 transcription remain to be elucidated, but preliminary evidence suggests enhanced nitric oxide generatmn in bone cellsis involved. Since current statins are not well distributed to peripheral tissues beyond the liver, their therapeutic efficacy m patients remains to be detenined in randomized control trials. However. observational studies in patients treated with statins for lipid-lowering suggest that there are beneficial effects on subsequent fracture risk.
THERAPEUTIC POTENTIAL OF THE OPG/ODF SYSTEM m R Dunstan, Development, Amgen, Thousand Oaks, California, USA Regulation of bone resorption by homeostatic and pathological stimuli converges on the Osteoprotegerin (OPG), RANK and RANKLIODFI TRANCE/OPGL signaling pathway. RANKL is a cytokine essential for osteoclast differentiation with a role also in osteoclast activation and survival RANK is a TNFR superfamily member and is the signaling receptor for RANKL OPG is a soluble secreted decoy receptor which competes for binding of RANKL and inhibits osteoclast differentiation OPG knockout mice have severe osteoporosis Mice and activation deficient in RANK or RANKL lack osteoclasts and have severe osteopetrosis. RANK knockout mice and mice treated with high doses of OPG. are resistant to the calcemic and resorptive effects of osteotropic hormones and cytokines indicating they require RANKL signaling for their action. It is likely that increased expression of RANKL relative to OPG mediates stimulation of bone resorption b, hormones and inflammatory cytokines. Treatment of healthy postmenopausal women with a modified form of OPG profoundly suppresses levels of urinary N-telopeptide of collagen and other surrogate markers of bone resorption. Mutations in RANK that increase RANK signaling appear to be responsible for familial expansile osteolysis. These results confirm the importance of RANKL in human osteoclast biology. Defects in RANK signaling may be involved in some cases of human osteopetrosis or Pagets disease of bone but this has not yet been confirmed. The essential requirement for RANKL for the activity of osteotropic hormones and cytokines suggests that OPG or other inhibitors of the RANK signaling pathway will be powerful inhibitors of pathological This has been supported by studies showing bone bone resorption protection by OPG in rodent models of hypercalcemia of malignancy, metastatic bone disease, inflammatory joint disease and ovariectomyrelated osteoporosis
131 CALCIIJM AND VITAMIN D P.J. Meunier - Department of Rheumatology and Bone Diseases. INSERM U 403, Edouard Herriot Hospital, Lyon, France. The most important nutrients for bone health are calcium and vitamin D. Calcium (Ca) functions as a threshold nutrient and below some critical value -about 800 mgiday- bone mass will be limited by available Ca supplies, whereas above that threshold no further benefit will accrue from additional increases in intake. More than 80 percent of elderly women have a dietary Ca intake below the recommended intake for postmenopausal women (1200mg/day). Vitamin D is particularly important for adaptation to low Ca intake. Serum 25(OH)D is the best functional indicator of vit.D status which depends on synthesis initiated by solar irradiation of the skin and dietary intake. Severe and long-lasting vit.D deficiency leads to frank osteomalacia. A less severe reduction in s.25(OH)D, named vit.D insnficiency, induces a secondary hyperparathyroidism which accelerates and bone loss, particularly in elderly subjects, Recent studies have shown that the s.2S(OH)D level corresponding to the lower limit of vit.D suf,ciency is much higher than the “classical“ threshold of 30nmol/l (or 12ng/ml). This reappraisal has two practical consequences : vit.D insufficiency, as defined by a s.25(OH)D below 70-8Omnol/l, is much more common than previously believed and this is relevant to larger possibilities of vit.D (or vit. D+Ca) supplements for preventing fractures by minimizing s. parathyroid hormone (PTH). Controlled studies performed in institutionalized elderly women (DECALYOS I and II studies) and in independent elderly subjects have demonstrated a significant protective effect against hip and non vertebral fractures of a combined supplement of Ca and vit.D. It is important to ensure that s.2S(OH)D level obtained after this supplementation reaches the threshold minimizing s.PTH. Correction of Ca and vit.D insufticiency should be the first step of any therapeutic strategy for OP.
132 NEW ESTROGENS. Robert Marcus, M.D. Stanford University Stanford CA USA. Despite enthusiasm for the SERM concept, only two, tamoxifen and raloxifene, now participate in the clinical marketplace. Others, such as droloxifene and idoxifene, were abandoned because of inadequate tissue selectivity (i.e. endometrial hyperplasia). New SERMs continue to undergo development for potential osteoporosis and breast cancer indications. These include Lasofoxifene and TSE-424. Delta 8,9dehydroestrone, a constituent of conjugated equine estrogens, is also tissue-selective and accounts for a non-trivial portion of the total estrogenic activity of this product. Although its effects are interesting, it does not appear destined for development as monotherapy. Current SERMs act as estrogen antagonists in the brain. Beyond implications for hot flashes lies persistent concern about adverse cognitive effects. No compelling data yet satisfy this concern. Tibolone, a complex molecule with estrogenic, androgenic, and progestational actions, Because of its appears close to approval in the United States. progestational effects, endomehial protection is not an issue, but reductions in HDL-cholesterol might be problematic. Phytoestrogens have captured the hearts and minds of many consumers. In high doses ipriflavone is a moderately effective antiresorptive agent. At doses available from health food stores, little if any effect on bone turnover is evident. 1998-9 was not a good time for HRT. Publications related to heart disease, Alzheimer’s disease, and breast cancer all increased public concern about estrogen toxicity. Many patients respond by trying lower doses and alternative products. In the absence of clear evidence that such strategies offer skeletal protection, it may be prudent to place those patients on a bisphosphonate, so that no matter what choices they make re. HRT, their bone will be protected.