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Figure 7 Chemical structure of estradiol, tamoxifen, and raloxifene. Tamoxifen and raloxiphene are selective estrogen receptor modulators (SERMs) approved for clinical use. Tamoxifen and raloxifene bind to the estrogen receptors, but are selective in the tissue responses induced.

Estradiol

Tamoxifen

Raloxifene

Figure 7 Chemical structure of estradiol, tamoxifen, and raloxifene. Tamoxifen and raloxiphene are selective estrogen receptor modulators (SERMs) approved for clinical use. Tamoxifen and raloxifene bind to the estrogen receptors, but are selective in the tissue responses induced.

the spines of osteoporotic postmenopausal women and also profoundly decreased the incidence of breast cancer. Added benefits of raloxifene over tamoxifen include the findings that raloxifene treatment elicited no changes in endometrial thickness, proliferation, or hyperplasia and there was no difference between raloxifene-treated women and placebo in incidences of vaginal discharge and spotting. There was also a trend towards a reduction in cognitive decline in elderly women treated with raloxifene as compared to placebo.63

6.21.6.2 Calcium and Vitamin D

6.21.6.2.1 Calcium

Calcium has long been used for the treatment of osteoporosis, both in the form of dietary and pharmacological supplements. In patients with calcium deficiency, oral calcium at doses of 500-1500 mg per day corrects a negative calcium balance and suppresses PTH secretion. Sufficient calcium intake is important for the accrual of peak bone mass in the young but is also considered the basis of most antiosteoporotic regimens. In the elderly, supplementation with oral calcium and vitamin D reduces the risk of hip fracture by about 30-40%. However, the majority of controlled studies have failed to show an effect of calcium supplementation alone on fracture risk in postmenopausal women.

6.21.6.2.2 Vitamin D

Vitamin D and its metabolites are widely recommended for the treatment of osteoporosis. Natural vitamin D3 (cholecalciferol) is synthesized in the skin through ultraviolet radiation (sun exposure) (Figure 3), while small amounts of vitamin D2 (ergocalciferol) are contained in the diet. Both components are metabolized, in the liver, to 25-hydroxyvitamin D (calcidiol) (Figure 3). The latter compound is considered the 'storage form' of vitamin D, and although it probably has little biological activity, calcidiol is measured in the clinical setting to determine whether a patient is deficient of this steroid hormone. The biologically active form of vitamin D is generated in the kidney through hydroxylation in position C1, leading to the formation of 1,25-dihydroxyvitamin D or calcitriol (Figure 3). The activity of the hydroxylating enzyme, 1a-hydroxylase, is tightly controlled by a number of regulators, including PTH or serum phosphate levels. 1,25-dihydroxyvitamin D is a potent steroid hormone with almost countless effects throughout the body, most concerning the differentiation of immature cells. As regards bone, 1,25-dihydroxyvitamin D has differentiation-inducing as well as activating effects on both osteoblasts and osteoclasts. It also increases the calcium absorption from the gut.

Data from some controlled clinical trials suggest that daily supplementation with 500-1200 mg calcium and 700-1000 IU of oral calciferol (not calcitriol!) reduces the rate of bone loss in postmenopausal women. Of note, institutionalized elderly persons with a high prevalence of secondary hyperparathyroidism due to calcium and vitamin D deficiency appear to benefit greatly from calcium and vitamin D supplementation: the landmark study by Chapuy et al.64 demonstrated that, in this elderly population, 1200 mg of calcium and 800 IU of vitamin D daily reduced the number of hip and nonvertebral fractures by 30%. In contrast, the recently published Randomised Evaluation of Calcium OR Vitamin D (RECORD) study failed to demonstrate a significant effect of oral calcium and vitamin D on osteoporotic fracture risk in men and women with prevalent low-trauma fractures (n = 5292 aged 70 years or older; 85% female).65

So-called 'active' vitamin D metabolites are still controversial with regard to their therapeutic use in postmenopausal and/or age-related osteoporosis. There is still no good evidence supporting the claim that, in postmenopausal or age-related osteoporosis, vitamin D metabolites such as 1a-hydroxy vitamin D or calcitriol are more efficacious with regard to bone loss or fracture reduction than either cholecalciferol or ergocalciferol. There is, however, evidence that calcitriol might be beneficial in certain secondary forms of osteoporosis, e.g., glucocorticoid-induced osteoporosis. While cholecalciferol and ergocalciferol have a broad therapeutic window with very few, if any, adverse effects, 'active' vitamin D metabolites are characterized by a narrow therapeutic window with hypercalciuria (kidney stones) and hypercalcemia being the most serious problems.

It should be noted that all of the recent drug trials used calcium and vitamin D as part of the therapeutic regimen (with the placebo group receiving calcium and vitamin D as active treatment) and that neither anabolic nor antiresorptive drugs should be given without calcium supplements.

Replacement of calcium and native vitamin D is critical when treating the most common form of osteomalacia, i.e., hypocalcemic osteomalacia, in the setting of severe vitamin D deficiency.

6.21.6.3 Anabolic Treatments

PTH has, for reasons that are not well defined, a dual effect on bone cells: given intermittently, PTH stimulates osteoblast activity, leading to substantial increases in bone density. In contrast, when secreted continuously at relatively high doses (as seen in patients with pHPT), PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium reabsorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxyvitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors, such as IGF-1 and TGFb Multiple signaling pathways mediating PTH effects on bone cells include activation of adenylyl cyclase, phospholipase C, protein kinase C, tyrosine kinase c-src, alterations in intracellular protein phosphorylation, and generation of inositol 1,4,5-triphosphate.

Recombinant human (rh)PTH(1-34) (teriparatide) increases bone mass, trabecular connectivity, and bone strength, improving BMD in females with postmenopausal osteoporosis, males with idiopathic osteoporosis, and in individuals with glucocorticoid-induced osteoporosis. There is currently only a single randomized controlled trial on rhPTH(1-34) in postmenopausal osteoporosis. In this 19-month-long study of 1637 women with prior osteoporotic vertebral fractures, 20 and 40 mg of rhPTH(1-34) subcutaneously reduced the risk of new vertebral fractures by 65-69% and the risk of nonvertebral fragility fractures by 53-54%. Concomitantly, lumbar spine BMD increased by 10-14% and femoral neck BMD by 3-5%.66 A comparative trial of teriparatide 40 mg subcutaneously versus alendronate 10 mg in women with postmenopausal osteoporosis showed that teriparatide was more potent than alendronate in increasing BMD and reducing fracture risk.67 While osteosarcomas have been observed in certain rat strains treated with high doses of rhPTH(1-34), these had no clinical relevance in humans. rhPTH 1-34 has recently been approved for the treatment of severe osteoporosis.

6.21.6.4 Strontium Salts

Strontium salts have long been investigated as anabolic agents for bone. In animals, strontium stimulates bone formation and substitutes for calcium in hydroxyapatite crystals. In humans, studies have shown increased bone mass (after correction of BMD values for strontium content) and a reduction in vertebral and, to a lesser degree, nonvertebral fractures.68 The mechanism of action of strontium salts is unknown and may involve modulation of calcium sensors or calcium channels.69

6.21.6.5 Fluoride

Fluoride ions stimulate bone formation by a direct mitogenic effect on osteoblasts altering hydroxyapatite crystals in the bone matrix. At low doses, fluorides induce lamellar bone, and at higher doses abnormal woven bone of inferior quality. The effect of fluorides on normal and abnormal (e.g., osteoporotic) bone is therefore dose-dependent. Fluoride has been used as a therapy for osteoporosis; however, clear benefit on fracture incidence has not been observed. Indeed, some high-dose studies have demonstrated increased fracture incidence.70 If fluoride is of benefit, it is within a very narrow therapeutic range.

6.21.7 Unmet Medical Needs and New Research Areas

6.21.7.1 Improved Evaluation of Fracture Risk

Accurate evaluation of fracture risk is currently an area of significant medical need. While BMD can be measured accurately, it defines only a proportion of fracture risk for an individual. Further risk can be identified from medical history, including previous fractures, by measuring surrogate markers of bone formation and resorption,71 identifying vitamin D deficiency, measuring muscle strength and balance skills, and by genetic analyses. There is a need for epidemiological studies to integrate these approaches to determine a global fracture risk to assist in treatment decisions

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