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General practitioners (GPs) in Denmark (n = 374) answered a questionnaire on attitudes toward including information on diet and sex in the prevention of coronary artery disease, cancers, osteoporosis, and weight problems. Risk factors for disease were ranked as follows: smoking, alcohol, stress, diet, physical exercise, heredity, and hygiene. Patients' lack of motivation, insufficient time for each patient, and inadequate knowledge about nutrition were listed by GPs as barriers to dietary counseling. GPs stated that the sex of the patient was important only for counseling on osteoporosis. Lack of time and insufficient knowledge were perceived as barriers to including sex-specific issues in prevention. One-half of the GPs were questioned about the issue of prevention on the basis of female case stories and the other half on the basis of male case stories with identical wording. Responses to the case stories indicated that GPs would give dietary guidance and recommend loss of weight to slightly overweight male patients to a much greater degree than to overweight female patients for prevention of coronary artery disease, give dietary counseling and recommend loss of weight and exercise to female patients more than to male patients for prevention of cancers, recommend a supplement of calcium and vitamin D for prevention of osteoporosis to female patients, and recommend weight gain and discuss psychosocial issues more with underweight female patients than with underweight male patients. Female GPs included measures of prevention such as dietary counseling, exercise prescription, dietary supplement prescription, and discussion of psychosocial issues to a greater extent than did male GPs.

Long-term antiresorptives use has been linked to atypical subtrochanteric and diaphyseal femoral fractures (AFF), the pathogenesis of which is still unknown. In the present case report we present the results of analysis of bone chips from a 74-year old female patient that had been on alendronate, ibandronate and denosumab treatment, and who sustained an atypical femoral fracture, by histology, quantitative backscattered electron imaging, and Raman spectroscopic analysis.

Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12–24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide‐treated patients and bone formation at remodeling sites was higher with teriparatide than placebo.Introduction:Recombinant teriparatide [human PTH(1‐34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies.Materials and Methods:We studied the mechanisms underlying this bone‐forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF‐I and IGF‐II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 μg or placebo for 12–24 months (median, 19.8 months) in the Fracture Prevention Trial.Results:A dose‐dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose‐dependent relationship in IGF‐II immunoreactive staining at all bone envelopes studied. The greater local IGF‐II presence after treatment with teriparatide may play a key role in stimulating bone formation.Conclusions:Direct evidence is presented that 12–24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.

An 18‐month randomized double‐blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once‐daily teriparatide 20 μg with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment.

Osteoprotegerin (OPG) is a soluble receptor for RANKL and therefore a competitive inhibitor of osteoclast differentiation and activity. With this key role in the control of resorptive activity, we found that OPG is a candidate gene for genetic control of bone mass. We examined the promoter and the five exons with surrounding intron sequences of the OPG gene for polymorphisms in 50 normal patients and 50 patients with osteoporosis. We found 12 polymorphisms. Two sets of four and five polymorphisms, respectively, were in complete linkage. Subsequently, we examined the effect of the informative polymorphisms A163‐G (promoter), T245‐G (promoter), T950‐C (promoter), G1181‐C (exon 1), and A6890‐C (intron 4) on the prevalence of osteoporotic fractures, bone mass, and bone turnover in 268 osteoporotic patients and 327 normal controls. In A163‐G the variant allele Gwas more common among fracture patients: 34.0% versus 26.3% in normal controls (p< 0.05) and the odds ratio (OR) for a vertebral fracture, if an individual has the Gallele, was 1.44 (1.00–2.08). In T245‐G the variant allele Gwas more common in osteoporotic patients: 12.4% versus 6.5% (p< 0.02) and the OR for vertebral fracture, if an individual has the G‐allele, was 2.00 (1.10–3.62). G1181‐C is located in the first exon and causes a shift in the third amino acid from lysine to asparagine. The CCgenotype was less common among fracture patients: 26.3% versus 36.7% in the normal controls (p< 0.01). T950‐C and A6890‐C were not distributed differently among patients with osteoporosis and normal controls. None of the polymorphisms affected bone mineral density (BMD) or biochemical markers of bone turnover in the normal controls. In conclusion, we have examined the human OPG gene for polymorphisms and found 12. The rare alleles of the A163‐G and T245‐G were significantly more common among patients with vertebral fractures.

We describe a sinus, referred to as a bone remodeling compartment (BRC), which is intimately associated with cancellous bone remodeling. The compartment is lined on its marrow side by flattened cells and on its osseous side by the remodeling bone surface, resembling a roof of flattened cells covering the bone surface. The flat marrow lining cells are in continuity with the bone lining cells at the margins of the BRC. We examined a large number of diagnostic bone biopsy specimens received during recent years in the department. Furthermore, 10 patients (8 women and 2 men, median age 56 [40–69] years) with the high turnover disease of primary hyperparathyroidism who were treated with parathyroidectomy and followed for 3 years were included in the histomorphometric study. Bone samples for the immuno‐enzyme staining were obtained from an amputated extremity of child. The total cancellous bone surface covered by BRC decreases by 50% (p< 0.05) following normalization of turnover and is paralleled by a similar 50% decrease in remodeling surface (p< 0.05). The entire eroded surface and two‐thirds of the osteoid surface are covered by a BRC. BRC‐covered uncompleted walls are 30% (p< 0.05) thinner than those without a BRC. This indicates that the BRC is invariably associated with the early phases of bone remodeling, that is, bone resorption, whereas it closes during the late part of bone formation. Immuno‐enzyme staining shows that the flat marrow lining cells are positive for alkaline phosphatase, osteocalcin, and osteonectin, suggesting that they are bone cells. The first step in cancellous bone remodeling is thought to be the lining cells digesting the unmineralized matrix membrane followed by their disappearance and the arrival of the bone multicellular unit (BMU). We suggest that the lining cell barrier persists during bone remodeling; that the old lining cells become the marrow lining cells, allowing bone resorption and bone formation to proceed under a common roof of lining cells; that, at the end of bone formation, new bone lining cells derived from the flattened osteoblasts replace the marrow lining cells thereby closing the BRC; and that the two layers of lining cells eventually becomes a single layer. The integrity of the osteocyte‐lining cell system is reestablished by the new generation of lining cells. The BRC most likely serves multiple purposes, including efficient exchange of matrix constituents and minerals, routing, monitoring, or modulating bone cell recruitment, and possibly the anatomical basis for the coupling of bone remodeling.

Estrogen and the estrogen receptor (ER) play a central role in bone metabolism as illustrated by the loss of bone mass after menopause and the osteopenia in individuals with defect aromatase or ER. We therefore wanted to investigate the effect of polymorphisms in the ER‐α gene on bone mass, bone turnover, and the prevalence of osteoporotic fractures in a study of 160 women and 30 men with vertebral fractures and 124 women and 64 men who are normal. Three previously described polymorphisms, G261‐C in exon 1 and T‐C and A‐G in intron 1, in the ER gene were determined by restriction fragment length polymorphism (RFLP) using BstUI, PvuII, and XbaI after polymerase chain reaction (PCR). A TA repeat polymorphism in the promoter region was examined by PCR and electrophoresis. The distribution of BstUI, PvuII, and XbaI RFLPs was similar in the osteoporotic patients and the normal controls. No significant differences could be shown in bone mass or bone turnover between the genotypes. The mean number of TA repeats was lower in patients with osteoporotic fractures, 17.3 ± 2.8 versus 18.6 ± 2.8 in the normal controls (p< 0.01). This also was reflected in a significantly increased odds ratio of osteoporotic fractures in individuals with 11–18 repeats of 2.64 (95% CIs, 1.61‐4.34). Furthermore, bone mineral density (BMD) of the lumbar spine was lower in individuals with low mean number of repeats than in individuals with high mean number of repeats (0.790 ± 0.184 g/cm2vs. 0.843 ± 0.191 g/cm2; p< 0.05). This difference also was found in BMD of the total hip. Using multiple linear regression, mean number of TA repeats was a predictor of lumbar spine BMD (p< 0.05) and a BMD‐independent predictor of fractures (p< 0.05). Mean number of TA repeats was not associated with levels of biochemical markers of bone turnover. All four polymorphisms were in linkage disequilibrium. A TA repeat polymorphism in the ER gene is associated with increased risk of osteoporotic fractures and a modest reduction in bone mass. Polymorphisms in the first exon and first intron of the ER gene are not associated with osteoporotic fractures, bone mass, or bone turnover.

Interleukin‐1β (IL‐1β) is a potent stimulator of bone resorption, and has been implicated in the pathogenesis of high bone turnover and osteoporosis. IL‐1 receptor antagonist (IL‐1ra) is a competitive inhibitor of IL‐1β effects and the biological effects of IL‐1β are therefore proportional to the ratio IL‐1β/IL‐1ra. The coding regions of IL‐1β were examined for sequence variations by SSCP and sequencing after polymerase chain reaction (PCR) of genomic DNA. Three previously described polymorphisms (C−511‐T, G3877‐A and C3954‐T) in the IL‐1β gene were determined by restriction fragment length polymorphism (RFLP) using AvaI, AciI, and TaqI after PCR. The 86‐base pair repeat polymorphism in IL‐1ra was examined by PCR and electrophoresis and the T11100‐C polymorphism in the IL‐1ra gene was examined by RFLP using MspA1I after PCR. All polymorphisms were related to bone mass, biochemical markers of bone turnover, and presence of fracture in a study including 389 osteoporotic patients with vertebral fractures and normal controls. Two normal women were heterozygous for a shift from cytosine to thymine (C3263‐T) in exon 4 of the IL‐1β gene. This substitution did not affect the amino acid sequence. We did not find other sequence variations in the IL‐1β gene apart from the already known polymorphisms. The distribution of C−511‐T, G3877‐A, and C3954‐T genotypes was similar in the osteoporotic and the normal controls. No significant differences could be shown in bone mass or bone turnover. In the IL‐1ra gene almost complete linkage was confirmed between the already known polymorphisms: G1731‐A, G1821‐A, A1868‐G, G1887‐C, T8006‐C, C8061‐T, 86 base pair variable number tandem repeat (VNTR), A9589‐T, and a new polymorphism: T1934‐C. The A1A1/A3genotypes of the IL‐1ra VNTR polymorphism were significantly more frequent in osteoporotic patients (56.2%) compared with age‐matched normal controls (433%) (χ2= 4.09; p= 0.043). The relative risk of osteoporotic fractures was increased to 1.68 (95% CI, 1.01–2.77) in individuals with A1A1/A3genotypes. Bone mineral density (BMD) of the lumbar spine was reduced in individuals with A1A1/A3genotypes (p= 0.014, analysis of variance [ANOVA]). The difference in bone mass between A1A1/A3and A2A1/A2tended to increase with increasing age. T11100‐C genotypes were distributed similarly in osteoporotic patients and normal controls and the polymorphism was without effect on bone mass and biochemical markers of bone turnover. In conclusion, an 86‐base pair repeat polymorphism in the IL‐1ra gene is associated with increased risk of osteoporotic fractures. Other polymorphisms in the IL‐1ra and the IL‐1β genes are not associated with osteoporotic fractures or alterations in bone mass or bone turnover.

In a randomized, double blind, clinical prospective trial comprising 35 women treated with either hormone replacement therapy (HRT) (cyclic estradiol/norethisterone acetate) or placebo we performed histomorphometric studies on paired bone biopsies obtained before and after 2 years of treatment. Untreated women developed a progressively more negative balance at individual bone multicellular units (BMUs) (i.e., wall thickness‐erosion depth) (2.2 ± 1.7 μm vs. −5.7 ± 1.4 μm; p< 0.01), while women on HRT displayed preservation of bone balance (2.4 ± 2.4 μm vs. 2.5 ± 2.5 μm; NS). No significant differences in wall thickness between the two groups were demonstrable, but the untreated women developed a pronounced increase in erosion depth over 2 years (46.9 ± 1.8 μm vs. 52.0 ± 1.9 μm; p< 0.05), while the HRT group revealed no change (47.8 ± 2.7 μm vs. 44.6 ± 1.7 μm; NS). Furthermore, the placebo group displayed an increased osteoclastic erosion depth (17.8 ± 1.6 μm vs. 25.0 ± 1.7 μm; p< 0.001), compared with unchanged values in the HRT group (20.0 ± 1.6 μm vs. 16.9 ± 1.4 μm/day; NS). While the placebo group revealed a slight increase in volume referent resorption rate (35 ± 8% vs. 38 ± 8%; NS) the HRT group revealed a pronounced decrease (46 ± 8% vs. 28 ± 5%; p< 0.05). No significant changes in marrow star volume (an index of trabecular perforations) were demonstrable in either group. Our results demonstrate that bone remodeling in early postmenopausal women is characterized by progressive osteoclastic hyperactivity, which is reduced by cyclic HRT. This reduction of resorptive activity at the BMU level after HRT seems to precede the reduction in activation frequency demonstrated in previous studies on older postmenopausal women.

In a randomized, double blind, clinical prospective trial comprising 35 women treated with either hormone replacement therapy (HRT) (cyclic estradiol/norethisterone acetate) or placebo we performed histomorphometric studies on paired bone biopsies obtained before and after 2 years of treatment. Untreated women developed a progressively more negative balance at individual bone multicellular units (BMUs) (i.e., wall thickness‐erosion depth) (2.2 ± 1.7 μm vs. −5.7 ± 1.4 μm; p< 0.01), while women on HRT displayed preservation of bone balance (2.4 ± 2.4 μm vs. 2.5 ± 2.5 μm; NS). No significant differences in wall thickness between the two groups were demonstrable, but the untreated women developed a pronounced increase in erosion depth over 2 years (46.9 ± 1.8 μm vs. 52.0 ± 1.9 μm; p< 0.05), while the HRT group revealed no change (47.8 ± 2.7 μm vs. 44.6 ± 1.7 μm; NS). Furthermore, the placebo group displayed an increased osteoclastic erosion depth (17.8 ± 1.6 μm vs. 25.0 ± 1.7 μm; p< 0.001), compared with unchanged values in the HRT group (20.0 ± 1.6 μm vs. 16.9 ± 1.4 μm/day; NS). While the placebo group revealed a slight increase in volume referent resorption rate (35 ± 8% vs. 38 ± 8%; NS) the HRT group revealed a pronounced decrease (46 ± 8% vs. 28 ± 5%; p< 0.05). No significant changes in marrow star volume (an index of trabecular perforations) were demonstrable in either group. Our results demonstrate that bone remodeling in early postmenopausal women is characterized by progressive osteoclastic hyperactivity, which is reduced by cyclic HRT. This reduction of resorptive activity at the BMU level after HRT seems to precede the reduction in activation frequency demonstrated in previous studies on older postmenopausal women.

In order to secure the mechanical integrity of the skeleton bone undergoes constant renewal throughout life. This renewal process, bone remodeling, consists of the continuos removal of bone (bone resorption) followed by synthesis of new bone matrix and subsequent mineralization (bone formation). Bone remodeling is also an integral part of the calcium homeostatic system together with the kidneys and the gut.

In this study we tested the effects of sodium fluoride (NaF) in serum‐free cultures of human marrow stromal osteoblast‐like [hMS(OB)] cells. NaF (10−5M) stimulated hMS(OB) cell proliferation up to 220% of control cultures. NaF alone did not increase type I collagen production, but in the presence of 1,25‐dihydroxyvitamin D3[1,25‐(OH)2D3] (10−9M), NaF enhanced type I collagen production in a dose‐dependent way to 300% of 1,25‐(OH)2D3‐treated control cultures. The production of alkaline phosphatase (ALP) and osteocalcin (bone gla protein, BGP) was also enhanced in the presence of 1,25‐(OH)2D3to 170 and 200%, respectively, of 1,25‐(OH)2D3‐treated controls. Our results suggest that 1,25‐(OH)2D3potentiates fluoride‐mediated anabolism in hMS(OB) cell cultures and suggest that osteoblast precursors in bone marrow are targets for fluoride action.

Thyroid hormones exert major influences on bone and mineral metabolism. Hyperthyroidism induces an accelerated bone loss and may thereby increase the risk of low-energy fractures. Hypothyroidism has the opposite effect. This review describes the effect of thyroid hormones on bone and mineral metabolism at the cellular, tissue, and organ level. Clinical aspects of disturbed thyroid function on bone metabolism also are discussed.

Advances in stereology have enabled us to substitute simple surface-based histomorphometry with pertinent derived variables that reveal much more about the processes taking place. Bone histomorphometry involves systematic, unbiased counting and measuring of tissue constituents and has yielded important information on bone remodeling in a wide variety of metabolic bone diseases. This article provides an update on the newest techniques of quantitative bone histology and the data obtained thus far using these techniques.

Bone remodeling constitutes the life-long renewal process of bone whereby the mechanical integrity of the skeleton is preserved. It implies the continuous removal of bone (bone resorption) followed by synthesis of new bone matrix and subsequent mineralization (bone formation). Moreover, bone remodeling is an integral part of the calcium homeostatic system together with the kidneys and the gut. The ever ongoing removal of old bone by osteoclastic resorption and subsequent coupled osteoblastic formation of new bone leads to liberation of calcium and matrix constituents into the serum. The matrix constituents liberated into the blood during bone resorption can be used as markers of bone resorption in serum or urine and components liberated during osteoblastic matrix synthesis are putative markers of bone formation.Extensive research over the last 10 years has characterized a wide variety of new markers of cellular activity in bone (Table 1). Serum and urine levels of these

Although bisphosphonates do inhibit bone resorption in postmenopausal women and lessen the risk of vertebral and hip fractures, as many as half of patients no longer adhere to prescribed oral treatment after 12 months. A single intravenous infusion of zoledronic acid reportedly decreases bone turnover and improves bone mineral density (BMD) for at least a year. In the HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly) Pivotal Fracture Trial, an international, randomized, double-blind, placebo-controlled study, postmenopausal women ranging in age from 65 to 89 years were assigned to receive either a 15-minute IV infusion of 5 mg of zoledronic acid or placebo at yearly intervals up to 24 months. All women received a daily supplement of 1000–1500 mg of calcium and 400–1200 IU of vitamin D. Participants had a bone mineral density (BMD) T score of −2.5 or less at the femoral neck or a score of −1.5 or less with 1 or more vertebral fractures. The efficacy analysis included 7736 patients, and the safety analysis, 7714 patients.