The biological role of strontium.

This review summarises old and more recent literature on the biological role of the bone-seeking trace metal strontium (Sr). It covers areas of chemistry, nutrition, toxicity, transport across biological membranes, homeostasis, general physiology, calcium-strontium interactions, and particularly the role of strontium in bone. The promoting action of strontium on calcium uptake into bone at moderate strontium supplementation, and the rachitogenic action of strontium at higher dietary strontium levels are emphasised. The literature is summarised of the novel antiosteoporotic drug strontium ranelate, which appears to act by a combination of reduced bone resorption and increased uptake of calcium into bone.

Response rates to oestrogen treatment in perimenopausal women: 5-year data from the Danish Osteoporosis Prevention Study (DOPS).

OBJECTIVE: To characterise women with no response or with a good response to hormone replacement therapy (HRT), evaluated by change in bone mineral density (BMD). DESIGN: Nested case-control study within a comprehensive cohort study. SUBJECTS AND METHODS: In the Danish Osteoporosis Prevention Study (DOPS), perimenopausal women were allocated to either HRT or no HRT. In the present study, we included 466 women who had been treated with HRT for 5 years and 466 untreated women from the same cohort. Non-responders were women in the treatment group, who decreased in BMD more than the mean decrease observed in the untreated group. Good responders were women with a larger increase in BMD than the upper 95% percentile of untreated women. Baseline characteristics were evaluated as predictors of response to HRT. RESULTS: 8.4 and 5.6% were classified as non-responders, whereas 25 and 57% were good responders according to changes in BMD of the femoral neck and lumbar spine, respectively. Combining measuring sites, 2.6% were non-responders and 20% were good responders. Non-responders at the femoral neck were more often smokers and had a lower spine BMD. Good responders were older, had a higher body weight, and higher alcohol consumption. In addition, good responders at both measurements sites had a lower BMD at the total hip. CONCLUSION: A favourable BMD response to HRT can be expected in most post-menopausal women especially if they are non-smokers with a moderate--as opposed to low--alcohol intake, a high body mass and a low initial hip BMD.

When should densitometry be repeated in healthy peri- and postmenopausal women: the Danish osteoporosis prevention study.

Intervention should be considered in postmenopausal women with bone mineral density (BMD) > or = 1 SD below the reference (T or Z score < -1). However, it is unclear when densitometry should be repeated. This study aimed at determining the need for repeat DXA within 5 years in untreated peri-/postmenopausal women to detect declines of T or Z score to below -1 with 85% confidence. A cohort of 925 healthy women (aged 51.2 +/- 2.9 years) were followed within the Danish Osteoporosis Prevention Study (DOPS) for 5 years without hormone-replacement therapy (HRT). DXA of spine, hip, and forearm was done at 0,1, 2, 3, and 5 years (Hologic QDR-1000/2000). The annual loss in SD units was 0.12 +/- 0.10 at the spine (1.3%), 0.10 +/- 0.09 at the femoral neck (1.2%), and 0.07 +/- 0.09 at the ultradistal (UD) forearm (1.0%). Accordingly, T scores below -1 developed earlier at the spine. The need for a future DXA scan to predict declines of T and Z scores below -1 depended strongly on baseline BMD. In subjects with a positive T score, the risk of developing T < -1 remained at <15% for 5 years at all measured sites. A new scan was needed after 1 year if the T score was below -0.5, and after 3 years if the T score was between 0 and -0.5. Slightly longer intervals apply if Z scores are used. Follow-up densitometry in untreated women should be individually targeted from baseline BMD rather than scheduled at fixed time intervals. An algorithm for planning repeat densitometry in perimenopausal women is provided.

Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis--a 2-year randomized placebo controlled trial.

The aim of the strontium ranelate (SR) for treatment of osteoporosis (STRATOS) trial was to investigate the efficacy and safety of different doses of SR, a novel agent in the treatment of postmenopausal osteoporosis. A randomized, multicenter, double-blind, placebo-controlled trial was undertaken in 353 osteoporotic women with at least one previous vertebral fracture and a lumbar T-score <-2.4. Patients were randomized to receive placebo, 0.5 g, 1 g, or 2 g SR/d for 2 yr. The primary efficacy endpoint was lumbar bone mineral density (BMD), assessed by dual-energy x-ray absorptiometry. Secondary outcome measures included femoral BMD, incidence of new vertebral deformities, and biochemical markers of bone metabolism. Lumbar BMD, adjusted for bone strontium content, increased in a dose-dependent manner in the intention-to-treat population: mean annual slope increased from 1.4% with 0.5 g/d SR to 3.0% with 2 g/d SR, which was significantly higher than placebo (P < 0.01). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment with 2 g/d SR [relative risk 0.56; 95% confidence interval (0.35; 0.89)]. In the 2 g/d group, there was a significant increase in serum levels of bone alkaline phosphatase, whereas urinary excretion of cross-linked N-telopeptide, a marker of bone resorption, was lower with SR than with placebo. All tested doses were well tolerated; the 2 g/d dose was considered to offer the best combination of efficacy and safety. In conclusion, SR therapy increased vertebral BMD and reduced the incidence of vertebral fractures.

Evaluation of methods for prediction of bone mineral density by clinical and biochemical variables in perimenopausal women.

OBJECTIVES: to predict spinal and femoral bone mineral density (BMD) in perimenopausal women from simple clinical and biochemical variables. METHODS: 2016 women 3-24 months past last menstrual bleeding. Mean age 50.1+/-2.8 years. Age, height, weight, number of full term pregnancies, weekly hours of physical activity, sunbathing habits, use of sun bed, daily intake of calcium and vitamin D, smoking habits, consumption of alcohol, coffee, and tea, history of forearm or femoral neck fractures among the parents, serum osteocalcin (S-OC), serum bone specific isoenzyme of alkaline phosphatase (BSAP), and urine hydroxyproline/creatinine ratio (U-OHP) were used as predictors in three different mathematical models. Lumbar spine (L2-L4) and femoral neck BMD were measured by DEXA. Three mathematical models (multiple regression, logistic regression, and discriminant analysis) were applied. RESULTS: the multiple regression explained 19-21% of the total variation, and the logistic regression and discriminant function had a sensitivity between 53 and 67% with specificity ranging from 67 to 80%. Age, S-OC, serum bone specific alkaline phosphatase, and a maternal history of forearm or femoral neck fractures seemed to be reproducible risk factors for low bone mineral density irrespective of the mathematical model applied. When applied to a separate population, the models performed poorly. CONCLUSIONS: Simple clinical and biochemical variables are not useful to predict spinal and femoral BMD in the individual perimenopausal woman.

Diagnosis of osteoporosis by planar bone densitometry: can body size be disregarded?

Bone densitometry using dual energy X-ray absorptiometry (DXA) is frequently used to diagnose osteoporosis and to identify patients at risk of later fractures. The parameters of interest are bone mineral content (BMC) and bone mineral areal density (BMD). Bone densitometry results have a large overlap between normals and patient with fractures. This would suggest that other factors are important for the development of fractures or that bone densitometry is not used optimally. It is generally believed that the conversion of BMC to BMD by division of the former by the projected bone area is a good normalization procedure. Other normalization procedures have been attempted in the past with little success. We hypothesized that this might be due to a blurring effect of time since menopause, and that body size could be demonstrated to have an effect on measured BMC and BMD, if this time effect could be eliminated. The results of this study, comprising 1625 early post-menopausal women studied at virtually the same time since menopause, confirm that this is the case. Body surface area was the parameter among conventional body size variables showing the highest correlation with BMC and BMD. It was clearly shown that low values of BMD were seen more often in the lowest than in the highest body surface area quartile. The difference between quartiles was statistically significant. Simple division of BMC by actual body surface area or division of BMD by the square root of body surface removed the uneven distribution between the body surface area quartiles for lumbar spine and femoral neck measurements, and reduced it at peripheral measuring sites. It is suggested that BMC and BMD of the lumbar spine and the femoral neck should be normalized as described to avoid overdiagnosis of osteoporosis in persons of petite body stature and underdiagnosis in tall ones.

Linearity and accuracy errors in bone densitometry.

This investigation was undertaken to quantify accuracy errors and identify possible linearity errors in dual energy X-ray absorptiometry (DXA) of bone, based on studies of commercially available bone densitometers for planar densitometry. The following was found in a combination of in vitro phantom studies and in vivo investigations of human volunteers: (1) Pronounced differences between the instruments when measuring vertebral size and contours of the projected bone regions. (2) Falsely low bone mineral content (BMC in terms of g) in cases of low nominal bone mass, due to the fact that edge regions were omitted by the calculation software of some devices. (3) An increase in the projected bone area secondary to an increase in nominal bone mass with some instruments. (4) Clinically and statistically significant errors of accuracy of BMC and to a lesser extent bone mineral density (BMD). (5) Substantial linearity errors with some osteodensitometers for BMC, a phenomenon that reduces the usefulness of this parameter. It is concluded that DXA devices are affected by a combination of accuracy errors and linearity errors, some more than others, and that linearity errors influence their ability to monitor change in BMC and to a lesser extent in BMD, making system intercomparison difficult.

A single measurement of biochemical markers of bone turnover has limited utility in the individual person.

Biochemical markers of bone turnover are used to estimate the rate of bone loss in the individual osteoporotic patient. During recent years it has become increasingly clear that the biological variability of biochemical bone markers has to be taken into consideration in the evaluation of their usefulness in the clinical setting. Eleven premenopausal, 8 perimenopausal and 11 postmenopausal healthy women were included. We assessed the analytical and the biological components of variation for a number of resorptive and formative bone markers: u-hydroxyproline, u-pyridinoline, and u-deoxypyridinoline together with u-calcium and u-creatinine, s-total alkaline phosphatases and s-osteocalcin. Blood and urine samples were collected five times with 7-day intervals. Urinary parameters were expressed as outputs and corrected for creatinine in fasting night urines and second void fasting morning urines. The absolute values differed with a tendency towards increasing values in the postmenopausal women, but the biological variations in relation to menopausal status were not different. The biological variability was much higher for the urinary resorptive markers than for the formative markers in the blood. The critical difference expressing the difference needed between two serial results from the same person to be significant at a 5% level was 15% for s-alkaline phosphatases, 18% for s-osteocalcin, and lowest in the second void fasting morning urines with values of 28% and 34% for u-pyridinoline/creatinine and u-deoxypyridinoline/creatinine, and 50% and 112% for u-hydroxyproline/creatinine and u-calcium/creatinine, respectively. The index of individuality, denoting the individual variation divided by the variation between subjects, was in the range from 0.19 for s-alkaline phosphatases to 1.23 for u-hydroxyproline/minute in second void fasting morning urine making the use of conventional reference intervals difficult. Low indices, however, indicate high test performance and offer the possibility of stratification of persons within a range. The number of samples required to determine the true individual mean value +/- 5% for the single person, ranged from 5 for s-total alkaline phosphatases, 6 for s-osteocalcin, 23 for u-deoxypyridinoline/creatinine in the fasting morning urine to over two hundred for u-calcium analytes. It is concluded that, due to high biological variation, a single measurement of biochemical markers of bone turnover is of limited utility in the individual person. We recommend that routine clinical use of biochemical markers should be restricted until further evidence justifies it.

Switching from DXA pencil-beam to fan-beam. II: Studies in vivo.

Switching from the Hologic QDR-1000/W to the QDR-2000 DXA densitometer was critically evaluated with regard to cross-calibration and dosimetry. Studies with bone equivalent humanoid spine phantoms and patient studies were done. Fan-beam scanning with the QDR-2000 is problematic because of magnification. Mean phantom bone mineral content (BMC) and bone mineral density (BMD) were moderately but significantly different. Biological variation disguised differences between the two devices in humans, but significant differences were revealed when individual data were analyzed. Longitudinal assessments of BMC and BMD, initiated with QDR-1000/W and continued with the QDR-2000, should employ single-beam mode only and not fan-beam mode--but even if that is done, significant errors can be introduced. The new QDR-2000 should be properly cross-calibrated with the original densitometer, and one should make sure that the same software, phantom, and type of collimator are used. The radiation dose is substantially higher with QDR-2000 (fan-beam and high-resolution array mode) than with QDR-1000/W (pencil-beam mode) and QDR-2000 (pencil-beam mode), and higher than claimed by the manufacturer. The typical radiation dose given by the manufacturer was half the actual radiation dose measured (e.g., for fan-beam scan 62 microSv versus 33 microSv). High-resolution array mode does not improve precision, but augments the radiation dose to the patient.

Switching from DXA pencil-beam to fan-beam. I: Studies in vitro at four centers.

The performance of the Hologic QDR-2000 DXA osteodensitometer was critically evaluated at four centers, using at all four centers one bone equivalent humanoid spine phantom supplied by the manufacturer. Results were compared with results from Hologic QDR-1000/W using that phantom tested at the same centers. It appears that the concept of fan-beam scanning--as used in the QDR-2000: a fan-beam, a linear array detector above the phantom, and an x-ray tube located rather close to the spine below the phantom--creates problems due to the magnification effect of the fan beam. The effect of decreasing the distance between the "vertebrae" of the phantom and the couch are: bone mineral content (BMC) increases by 2.8% per cm, projected area (Area) by 2.8% per cm, and bone mineral density (BMD) is unchanged. When QDR-1000/W is upgraded to QDR-2000, BMD is relatively constant, but there are shifts of BMC and Area which are partly due to the magnification effect of the fan-beam. Replacement of a QDR-1000/W with a QDR-2000 can invalidate longitudinal measurements, even for BMD, unless the proportionality factors of the QDR-2000 are checked and, if necessary, changed. This is true for switching from QDR-1000/W to pencil-beam mode of QDR-2000 or to fan-beam mode of QDR-2000. Even with pencil-beam mode, the long-term precision error with phantoms is higher for QDR-2000 than for QDR-1000/W (for BMD, 0.47% versus 0.35%).

Magnitude and pattern of skeletal response to long term continuous and cyclic sequential oestrogen/progestin treatment.

OBJECTIVE: To investigate the magnitude and pattern of the changes in bone mass during five years of continuous and cyclic sequential oestrogen/progestin treatment. DESIGN: Prospective study of normal, early postmenopausal women, initially a double-blind, placebo controlled trial, subsequently an open, controlled investigation. SETTING: Clinical physiology unit of a general hospital. SUBJECTS: Sixty-eight normal, early postmenopausal women. RESULTS: 1. Continuous treatment resulted in significantly higher lumbar spine bone density than did sequential treatment (P < 0.001). Lumbar spine bone density was 19% and 15%, respectively, above that of untreated women after three years and onwards, and 10% and 6%, respectively, above the initial value; 2. Both regimens induced a more pronounced rise in lumbar spine bone density than in forearm bone mineral content (P < 0.001); 3. The spontaneous decline (without treatment) in lumbar spine bone density and forearm bone mineral content averaged 1.86% and 1.90% per year, respectively. 4. There was a significant bone loss from the lumbar spine during the last year of active treatment (P < 0.001). This would suggest that lumbar spine bone density rises to a certain level and subsequently declines. However, neither data pooled before computation nor data processed individually for each patient over five years allowed for any definite conclusions regarding the pattern of the long term skeletal response to combined oestrogen/progestin treatment. CONCLUSION: Five years treatment with oestradiol/norethisterone resulted in a substantial gain in bone mass. The highest values were found in the axial skeleton with daily administration of 2 mg oestradiol and 1 mg norethisterone. It is likely that bone mass after an absolute rise begins to decline after about four years of treatment.

Reversal of postmenopausal vertebral bone loss by oestrogen and progestogen: a double blind placebo controlled study.

Because of uncertainty about the place of hormones in the treatment of postmenopausal bone loss vertebral and forearm bone loss was measured by absorptiometry in early postmenopausal women before and after continuous or sequential treatment with combined oestrogen and progestogen in a double blind placebo controlled trial. Treatment with hormones significantly reversed the vertebral bone loss. The net gain in vertebral bone density amounted to 6.4% a year with continuous supplementation and 5.4% a year with sequential supplementation; the net gain in forearm bone density was lower (3.6% with continuous and 3.7% with sequential supplementation). Before a policy of supplementation with hormones can be recommended to all postmenopausal women with the aim of reducing the incidence of vertebral crush fractures further studies with different doses and combinations of hormones, administered over several years, are needed.

Physical exercise as prophylaxis against involutional vertebral bone loss: a controlled trial.

1. The skeletal effects of physical training were studied in a controlled trial involving 31 healthy women (aged 50-73 years) with previous Colles' fracture of the forearm. The bone mineral content of the lumbar spine and both distal forearms was measured by dual-photon (153Gd) absorptiometry. 2. The participants were allocated to either a physical exercise group or a control group. The former group followed a standardized exercise programme, exercising for 1 h twice weekly during 8 months. 3. Twenty-seven women completed the study. Lumbar spine bone mineral content of the exercise group increased by 3.5%, whereas that of the control group decreased by 2.7%. The rate of bone loss in the control group equalled that of age-matched normal women. 4. The changes in forearm bone mineral content appeared to be independent of the exercise. The bone mineral content of the previously fractured forearm remained nearly unchanged. The bone mineral content of the uninjured forearm decreased on average by 3.5%. 5. The data suggest that physical exercise can inhibit or reverse the involutional bone loss from the lumbar vertebrae in normal women. Physical exercise may prevent spinal osteoporosis.

Bone mineral content of the lumbar spine in normal and osteoporotic women: cross-sectional and longitudinal studies.

1. Bone mineral content of the second, third and fourth lumbar vertebrae was determined in normal women and women with clinical osteoporosis by using dual-photon (153Gd) absorption. 2. A cross-sectional study of 70 normal (aged 19-88 years) showed a bone loss of 44% from the age of around 34 years throughout life. 3. Longitudinal data from 59 normal women confirmed that the vertebral bone loss started before the menopause. An accelerated bone loss amounting to nearly 6% per year was seen immediately after the menopause. The bone loss of older women was slower. 4. Mean lumbar bone mineral content of 36 women (aged 48-93 years) with recent fractures of their femoral neck after minor trauma equalled that of aged-matched normal women. Lumbar bone mineral content of the women with intratrochanteric femoral neck fractures was lower than that of the women with medial femoral neck fractures. 5. Mean lumbar bone mineral content of 72 women (aged 58-59 years) with primary osteoporosis was 41% lower than that of normal premenopausal women and 18% lower than that of age-matched controls. A weak inverse relationship between lumbar bone mineral content and the number of compression fractures was found. A weak inverse relationship between lumbar bone mineral content and the number of compression fractures was found. 6. Women with lumbar bone mineral content values below the 95% confidence limits for normal premenopausal women are at risk of future vertebral compression fractures, the fracture risk being inversely related to lumbar bone mineral content.

Assessment of vertebral osteopenia. Comparison of spinal radiography and dual-photon absorptiometry.

A comparison of radiographic morphology and dual-photon (153Gd) absorptiometry was carried out in 132 women. Films of the lumbar spine were graded for osteopenia, spondylosis, and calcification of the abdominal aorta according to definite morphologic criteria. The radiographic grade of osteopenia and the bone mineral content of the 2nd, 3rd, and 4th lumbar vertebrae showed a highly significant inverse correlation. However, the mineral content at each radiographic grade of osteopenia differed considerably. Disproportionately high levels occurred in patients with spondylosis and severe calcification of the abdominal aorta. Spinal radiography and dual-photon absorptiometry must be regarded as complementary rather than alternative diagnostic procedures in clinical practice.

Measurement of bone mineral content (BMC) of the lumbar spine, I. Theory and application of a new two-dimensional dual-photon attenuation method.

A new scanning dual-photon attenuation method utilizing a 153Gadolinium point source has been evaluated. The method allows precise in vivo determination of the bone mineral content of the lumbar spine (lumbar BMC). Lumbar BMC is expressed as the sum of the scan integrals of the second, third, and fourth lumbar vertebrae. The influence of crush fractures and varying amounts of soft tissue and fat is negligible. The coefficient of variation of repeated measurements ranges from 1.4% in normal pre-menopausal women to 2.6% in post-menopausal women with clinical osteoporosis. The radiation dose is low. The method is suited for cross-sectional and longitudinal studies of patients with lumbar osteopenia.

Measurement of bone mineral content (BMC) of the lumbar spine, II. correlation between forearm BMC and lumbar spine BMC.

A comparison between forearm bone mineral content (BMC) and lumbar BMC was made in post-menopausal women. Women without symptoms, women with clinical spinal osteoporosis, and women with prednisone-treated rheumatoid arthritis were studied. A conventional two-dimensional single-photon osteodensitometer was used for measurement of forearm BMC. A new two-dimensional dual-photon osteodensitometer was used for measurement of lumbar BMC. Its radioactive source was 153Gadolinium. The mean lumbar BMC was significantly reduced in women with clinical spinal osteoporosis (P < 0.001). The mean forearm of BMC of those patients was normal. Thus, forearm BMC was a poor indicator of spinal osteopenia. If forearm BMC was used to predict lumbar BMC erroneously high results were obtained in women with clinical spinal osteoporosis, and erroneously low values were obtained in prednisone-treated women with rheumatoid arthritis.