J. Coen Netelenbos

Estrogen Regulation of Intestinal Calcium Absorption in the Intact and Ovariectomized Adult Rat

Studies were carried out to examine the mechanism of action of estrogen on intestinal calcium absorption in the rat. Three‐month‐old Wistar rats were sham‐operated or ovariectomized (OVX). They were fed a diet containing 0.4% Ca, 0.4% P, and 2000 IU vitamin D3/kg. Eight weeks after operation, both OVX and sham‐operated rats were randomly assigned to eight treatment groups. Five groups received per 100 g of body weight 12.5 ng calcitriol (1,25‐dihydroxyvitamin D3); 7.5 μg of estradiol‐benzoate; 7.5 μg of estradiol‐benzoate and 0.1 mg of ICI 182780; 12.5 ng of calcitriol and 0.1 mg of ICI 182780; and 0.1 mg of ICI 182780, respectively. Three groups received the various vehicles used. Intestinal calcium absorption was measured in vivo using single pass perfusion of the duodenum. OVX did not change intestinal calcium absorption. A pharmacological dose of estradiol‐benzoate caused a significant increase in intestinal absorption of calcium, which was comparable to that of a pharmacological dose of calcitriol in both OVX and sham‐operated rats. Estrogen‐induced rise in intestinal calcium absorption was completely blocked to basal level by the pure estrogen receptor (ER) antagonist ICI 182780. In contrast, ICI 182780 did not antagonize calcitriol‐enhanced intestinal calcium absorption. Our findings suggest that estrogen stimulates intestinal calcium absorption via an ER.

Lower mobility and markers of bone resorption in the elderly.

Immobilization may lead to severe bone loss. Physical activity decreases with age and lower mobility might influence bone loss. We have evaluated the degree of mobility and parameters of bone turnover in 70 residents of a nursing home (mean age +/- SD 81 +/- 9 years) and 68 residents of an old peoples home (mean age +/- SD 84 +/- 6 years). The mobility was assessed with a standing and walking score from 1 (severely disabled) to 5 (standing/walking without help). When the subjects were arranged according to increasing walking score from 1 to 5, fasting urinary hydroxyproline/creatinine ratio gradually decreased from 31 +/- 19 to 14 +/- 5 mumol/mmol (P less than 0.001). There was also a significant linear decrease of fasting urinary calcium/creatinine ratio, and serum calcium concentration and a significant increase of serum albumin and 1,25-dihydroxyvitamin D concentrations with increasing walking score. These data indicate that lower mobility in the elderly leads to higher bone resorption, which may suppress the formation of 1,25-dihydroxyvitamin D.

Daily Oral Pamidronate in Women and Men With Osteoporosis: A 3-Year Randomized Placebo-Controlled Clinical Trial With a 2-Year Open Extension

The efficacy and safety of oral pamidronate was examined in a double‐blind, placebo‐controlled trial in women and men with established osteoporosis. Seventy‐eight postmenopausal women and 23 men with at least one prevalent vertebral fracture were randomized separately to 150 mg/day of pamidronate or placebo for 3 years followed by 150 mg/day of pamidronate for an additional 2 years. In addition, all patients received 400 U/day of cholecalciferol and 500 mg/day of elemental calcium. Pamidronate increased significantly bone mineral density of the lumbar spine (LS‐BMD) and of the femoral neck (FN‐BMD). The total increase in BMD of the spine after 5 years of treatment was 14.3%. Lateral spine radiographs were obtained at baseline and after 3 years of treatment. Fractures of previously normal vertebrae occurred in 15 of 45 patients treated with placebo (33.3%) and in 5 of 46 patients treated with pamidronate (11%). The relative risk was 0.33 (95% CI, 0.14‐0.77). Treatment was well tolerated and there was no difference in gastrointestinal toxicity between pamidronate and placebo‐treated patients. One hundred fifty milligrams daily of pamidronate is an effective and safe treatment of women and men with established osteoporosis.

Pubertal Maturation Characteristics and the Rate of Bone Mass Development Longitudinally Toward Menarche

To assess risks for osteoporosis and to compare bone mass in different groups of healthy children or children with diseases, it is important to have knowledge of their sexual maturation status during puberty. The aim of our study was to evaluate bone mass formation longitudinally in relation to pubertal maturation characteristics in healthy white girls. We investigated the bone mineral content (BMC) and the bone mineral density (BMD) at different skeletal sites in 151 girls with increasing pubertal stages in relation with their chronological age and with an early or late onset of puberty or menarche and with a slow or fast maturation. Bone mass was measured at the onset of puberty, during puberty, and at menarche. We conclude the following: (1) from midpuberty to menarche, the increase in bone mass formation is highest at all skeletal sites in white girls; (2) early mature girls at the onset of puberty have slightly but definitely lower bone masses at all skeletal sites and at all pubertal stages than late mature girls, whereas the average bone mass formation from the onset of puberty to menarche is similar in both groups; (3) girls with a slow rate of pubertal maturation have lower bone mass values 2 years after the onset of puberty, but at menarche bone mass is similar compared with fast maturers; and (4) it cannot be confirmed that there is an effect of menarcheal age on bone mass values at menarche.

A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVESnLipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT).nnnMETHODSnIn a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months.nnnRESULTSnThe mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05).nnnCONCLUSIONSnLong-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.

Effects of administration of 17β‐oestradiol on serum leptin levels in healthy postmenopausal women

Women have higher leptin levels than men at a certain degree of adiposity. The role of oestrogens in the regulation of serum leptin levels remains inconclusive. The aim of the present study was to investigate the effect of unopposed oestrogen replacement therapy, during two months, on serum leptin levels in postmenopausal women.

Continuously combined hormone replacement therapy and bone turnover: the influence of dydrogesterone dose, smoking and initial degree of bone turnover.

In this study we examined whether the effect of continuously combined hormone replacement therapy (HRT) on bone metabolism is influenced by dydrogesterone dose, smoking and initial degree of bone turnover. In a double-blind randomized study, 123 healthy postmenopausal women (mean age 51.7 years; range 30-61 years) received 17 beta-estradiol, 2 mg orally per day, continuously combined with either 2.5, 5, 10 or 15 mg of dydrogesterone daily. At baseline and at 3 and 6 months of therapy, bone formation was assessed by determining total alkaline phosphatase (TAP), bone-derived alkaline phosphatase (BAP), and the carboxy-terminal propeptide of collagen type I (PICP) in serum; bone resorption was assessed by the calcium/creatinine (Ca/Creat) and hydroxyproline/creatinine (Hp/Creat) ratio in 2-h fasting urine, and the serum carboxy-terminal pyridinolyne cross-linked telopeptide of collagen type I (ICTP). Dydrogesterone dose did not influence the effect of HRT on any of the bone markers. Combining the data of the four treatment groups, the decrease in each marker, compared to baseline values, was significant. However, in non-smokers, compared to smokers, after 6 months of therapy the decline in BAP and TAP was significantly more pronounced and the plasma estradiol level was significantly higher. For each bonemarker at baseline, women in the highest quartile, compared to women in the lowest quartile, showed a significantly stronger decrease in this marker in response to HRT. We conclude that dydrogesterone dose does not modify the effectiveness of replacement therapy. However, smoking and a low bone turnover at baseline may diminish its beneficial effect on bone.

Effect of estrogen on intestinal strontium absorption in postmenopausal women

OBJECTIVESnthere is considerable uncertainty about the underlying cause of decreased intestinal calcium absorption that occurs in postmenopausal women. In a previous study, estrogen treatment did not result in an increased intestinal calcium absorption using strontium as a marker. A possible explanation could be that the calcium/strontium load given to the women was too high ( approximately 600 mg Ca), which might result in an insensitive test with respect to the possible stimulation of active strontium transport by estrogen. Therefore, the purpose of this study was to reinvestigate the effect of estrogen on active intestinal strontium absorption using a load of 2.5 mmol of strontium only.nnnMETHODSnthe effect of estrogen on intestinal strontium absorption was measured in eight normal postmenopausal women. The study included two baseline strontium absorption tests, which were performed with an interval of 10 days for calculating the within subject variation (SER). Thereafter the effect of 2 months of estrogen treatment on intestinal strontium absorption was assessed. Fractional absorption (FC(240)) and the area under the concentration time curve (AUC) 4 h after an oral strontium load of 2.5 mmol were calculated.nnnRESULTSnthe within subject SER of FC(240) and AUC(0-240) were 2.3+/-0.76 and 1.2+/-0.41, respectively. FC(240) and AUC(0-240) of strontium were unchanged after treatment with estrogen.nnnCONCLUSIONSnin normal postmenopausal women, we did not find a modulating effect of short-term treatment with a (supra) physiological dose of estrogen on intestinal calcium absorption as measured by the strontium absorption test.

Clinical Utility Gene Card for: Fibrodysplasia ossificans progressiva

1.5 Mutational spectrum The spectrum described in this paragraph is based on RefSeq NM_001105.4. All patients have heterozygous ACVR1 missense mutations in conserved amino acids. This disease-causing variant is a de novo mutation and therefore referred to as a mutation. Patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G4A; p. (Arg206His)) in the ACVR1 gene leading to an over-activation of the BMP signalling pathway. Only recently a new heterozygous ACVR1 mutation at codon 207 (c.619C4G, p.(Gln207Glu)) located in a codon adjacent to the c.617G4A, p.(Arg206His) of the ACVR1 was reported in two FOP patients with the classical phenotype.4 Among patients with FOP-like heterotopic ossification and/or toe malformation, there are patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features, predominantly associated with the classical p.(Arg206His) mutation) and FOP variants (major variations in one or both of the two classic defining features of FOP, associated with non-Arg206His mutations within the ACVR1 receptor). Novel ACVR1mutations occur mainly in FOP variants and some cases of FOP plus.4–6 A public list of disease causing variants is not available yet.