In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization.

UNLABELLED: In postmenopausal osteoporotic women and up to 3 years of treatment with strontium ranelate, strontium was present only in recently deposited bone tissue resulting from formation activity during the period of treatment. Strontium was shown to be dose-dependently deposited into this newly formed bone with preservation of the mineralization. INTRODUCTION: Interactions between strontium (Sr) and bone mineral and its effects on mineralization were investigated in women treated with strontium ranelate. METHODS: Bone biopsies from osteoporotic women were obtained over 5-year strontium ranelate treatment from phases II and III studies. Bone samples obtained over 3-year treatment were investigated by X-ray microanalysis for bone Sr uptake and focal distribution, and by quantitative microradiography for degree of mineralization. On some samples, Sr distribution (X-ray cartography) was analyzed on whole sample surfaces and the percentage of bone surface containing Sr was calculated. Bone Sr content was chemically measured on whole samples. RESULTS: In treated women, Sr was exclusively present in bone formed during treatment; Sr deposition depended on the dose with higher focal content in new bone structural units than in old ones constantly devoid of Sr, even after 3-year treatment. A plateau in global bone Sr content was reached after 3 years of treatment. Cartography illustrated the extent of surfaces containing Sr, and formation activity during strontium ranelate treatment was higher in cancellous than in cortical bone. Mineralization was maintained during treatment. CONCLUSION: The quality of bone mineral was preserved after treatment with strontium ranelate, supporting the safety of this agent at the bone tissue level.

Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis.

SUMMARY: Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis. INTRODUCTION: Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate. METHODS: A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated. RESULTS: Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction = 0.67, p < 0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p < 0.001). QoL, assessed by the QUALIOST(R), was significantly better (p = 0.025), and patients without back pain were greater (p = 0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups. CONCLUSION: In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.

The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients.

Degree of mineralization of bone (DMB) is a major intrinsic determinant of bone strength at the tissue level but its contribution to the microhardness (Vickers indentation) at the intermediary level of organization of bone tissue, i.e., Bone Structural Units (BSUs), has never been assessed. The purpose of this study was to analyze the relationship between the microhardness, the DMB and the organic matrix, measured in BSUs from human iliac bone biopsies. Iliac bone samples from controls and osteoporotic patients (men and women), embedded in methyl methacrylate, were used. Using a Vickers indenter, microhardness (kg/mm2) was measured, either globally on surfaced blocks or focally on 100 microm-thick sections from bone samples (load of 25 g applied during 10 sec; CV=5%). The Vickers indenter was more suited than the Knoop indenter for a tissue like bone in which components are diversely oriented. Quantitative microradiography performed on 100 microm-thick sections, allowed measurement of parameters reflecting the DMB (g/cm3). Assessed on the whole bone sample, both microhardness and DMB were significantly lower (-10% and -7%, respectively) in osteoporotic patients versus controls (p<0.001). When measured separately at the BSU level, there were significant positive correlations between microhardness and DMB in controls (r2=0.36, p<0.0001) and osteoporotic patients (r2=0.43, p<0.0001). Mineralization is an important determinant of the microhardness, but did not explain all of its variance. To highlight the role of the organic matrix in bone quality, microhardness of both osteoid and adjacent calcified matrix were measured in iliac samples from subjects with osteomalacia. Microhardness of organic matrix is 3-fold lower than the microhardness of calcified tissue. In human calcanei, microhardness was significantly correlated with DMB (r2=0.33, p=0.02) and apparent Young's modulus (r2=0.26, p=0.03). In conclusion, bone microhardness measured by Vickers indentation is an interesting methodology for the evaluation of bone strength and its determinants at the BSU level. Bone microhardness is linked to Young's modulus of bone and is strongly correlated to mineralization, but the organic matrix accounts for about one third of its variance.

Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women.

It has been previously shown that the level of circulating undercarboxylated osteocalcin (ucOC) is elevated in elderly women in comparison with young, healthy, premenopausal ones. To understand the mechanism of the increase in the ucOC in the elderly and to assess its potential consequences on bone fragility, we have measured ucOC in the sera of 195 elderly institutionalized women 70-101 yr of age. In 45 women (23%) serum ucOC was above the upper limit of the normal range for young women. The level of ucOC was negatively correlated with 25OHD (r = -0.32, P < 0.001) even after excluding the effect of age, parathyroid hormone (PTH), and creatinine by partial correlation (r = -0.24, P < 0.002). During an 18-mo follow-up, 15 women sustained a hip fracture and their baseline ucOC level was higher (P < 0.01) in women who subsequently sustained hip fracture than in the nonfracture group contrasting with no significant differences for serum calcium, phosphate, alkaline phosphatase, creatinine, PTH, 250HD, and total and carboxylated OC. The risk of hip fracture was increased in women with elevated ucOC (relative ratio 5.9, 99.9% Cl 1.5-22.7, P < 0.001). During 1 yr of calcium/vitamin D2 treatment, ucOC decreased (P < 0.05), especially in those with the initially increased values (from 2.22 +/- 0.35 to 1.41 +/- 0.29 ng/ml, P <0.005) contrasting with an increase in the placebo group (P < 0.05). In conclusion, the increase in ucOC in the elderly reflects not only some degree of vitamin K deficiency but also their poor vitamin D status, suggesting that vitamin D may be important, either directly or indirectly through its effect on bone turnover, for achieving a normal gamma-carboxylation of OC. The ucOC, but not conventional calcium metabolism parameters, predicts the subsequent risk of hip fracture, suggesting that serum ucOC reflects some changes in bone matrix associated with increased fragility.

Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases.

The aim of this study was to determine the ability of disodium dichloromethylene diphosphonate (Cl2MDP) to reduce the hypercalcemia secondary to skeletal metastases and induced by stimulation of bone resorption by malignant cells. Five patients with hypercalcemia due to bone metastases of breast or renal cancer were treated orally for 4 wk with 3,200 mg of Cl2MDP and 4 wk with a placebo in a double blind, crossover study. During the Cl2MDP period of administration four patients experienced a rapid and significant decrease in serum calcium and urinary calcium excretion together with an increase in alkaline phosphatase. In the remaining patient who developed a sudden paraplegia at the onset of the therapy followed by a marked increase in serum calcium levels and urinary calcium excretion, Cl2MDP was able to reverse this worsening of hypercalcemia or to reduce serum and urinary calcium to normal values. For all patients, urinary hydroxyproline excretion was unchanged during the Cl2MDP period when compared with the prestudy or placebo periods. From these results, and because of the rapid relapse of hypercalcemia during the placebo period or after withdrawal of the treatment, we can conclude that Cl2MDP is capable of reducing excessive mobilization of calcium resulting from bone metastases.

Effects of disodium dichloromethylene diphosphonate on bone loss in paraplegic patients.

21 paraplegic patients with recent traumatic spinal cord injury were orally administered 400 (n = 7) or 1,600 (n = 7) mg/d of disodium dichloromethylene diphosphonate (Cl2MDP) and compared with a placebo group (n = 7) to test the preventive effects of the drug on acute bone loss and osteoclastic resorption. Cl2MDP therapy was initiated at a mean of 17.6 d after the onset of paraplegia. The study lasted at least 6 mo, consisting of a 3.5-mo treatment period, and a variable follow-up period. The effects of Cl2MDP were assessed by blood and urine biochemistry, bone histomorphometry on transilial samples, photon absorptiometry of the tibia and fibula, and radiomorphometry of the femur. The elevation in serum and urinary calcium and in urine hydroxyproline observed in the placebo group did not appear under treatment. With both doses of Cl2MDP there was no further decrease in the bone mineral content. In the treated groups, a smaller percentage increase in osteoclastic population was also noted when compared with the placebo group, but this difference was not significant. There was no mineralization defect induced by Cl2MDP, as shown by tetracycline double labeling. It thus appears that at doses ranging between 400 and 1,600 mg, given as early as possible, Cl2MDP can prevent or reduce the development of the acute bone loss of paraplegic patients, without adverse side effects, though it does not prevent the development of heterotopic ossification.

Serum bone gamma carboxyglutamic acid-containing protein in primary hyperparathyroidism and in malignant hypercalcemia. Comparison with bone histomorphometry.

Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (sBGP), a sensitive and specific marker of bone turnover, was measured in 25 patients with primary hyperparathyroidism and in 24 patients with bone metastases with or without hypercalcemia. Despite similar levels of hypercalcemia, sBGP was increased in primary hyperparathyroidism (14.2 +/- 9.6 ng/ml, P less than 0.001), was decreased in malignant hypercalcemia (3.1 +/- 2.8 ng/ml, P less than 0.001), and was normal in patients with bone metastases without hypercalcemia (6.6 +/- 2.7 ng/ml). In primary hyperparathyroidism, sBGP was correlated with serum immuno-reactive parathyroid hormone (r = 0.90), calcium (r = 0.73), and with the adenoma weight (r = 0.79). After parathyroidectomy, sBGP slowly returned to normal values within 2-6 mo, suggesting that sBGP reflects increased bone turnover rather than a direct effect of parathyroid hormone on BGP synthesis at the cell level. An iliac crest biopsy was performed in 11 patients with primary hyperparathyroidism and in 9 cancer patients in a noninvaded area. sBGP was significantly correlated with all parameters reflecting bone formation but not with bone resorption. Patients with bone metastases were analyzed according to the presence or the absence of hypercalcemia. In contrast to normocalcemic patients who had normal sBGP, hypercalcemic patients had decreased sBGP (P less than 0.001) and a lower bone formation at the cellular level (P less than 0.05). Thus, biochemical and histological data suggest that an unknown humoral factor might be responsible for this uncoupling between increased resorption and decreased formation. This uncoupling, rather than local release of calcium by the metastatic process, might be responsible for hypercalcemia in patients with bone metastases.

Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis.

Treatment effects on bone quality and remodeling was assessed in postmenopausal women with osteoporosis treated with oral alendronate. One transiliac bone biopsy was obtained from 231 women at either 24 mo (n = 11) or 36 mo (n = 120) from the start of treatment with alendronate at doses of between 5 and 20 mg/d, or placebo. 64 biopsies at 24 mo (31 from the placebo group and 33 alendronate-treated patients) and 95 biopsies at 36 mo (40 from the placebo group and 55 alendronate-treated patients) provided adequate cancellous tissue, and were analyzed by histomorphometry. Mineral apposition rate was unaffected by treatment. At 24 and 36 mo, osteoid thickness, volume, and surface significantly decreased. At each of the doses studied, mineralizing surface and activation frequency significantly decreased at each time point (e.g., -92% and -87%, respectively, for the 10 mg daily dose after 2 yr). These diminutions were of the same magnitude for each dose at 24 mo, and for the two highest doses at 36 mo. A significant increase in wall thickness accompanied by a reduction in erosion depth was detected in biopsies obtained at 24 mo. These findings confirm that mineralization is normal, and trabecular bone turnover markedly decreased in patients receiving long-term dosing with alendronate. The findings also suggest that the observed increases in bone mineral density could result both from a reduction in the remodeling space due to a decreased activation frequency and a possible trend to a positive bone balance. In addition, further studies focused on a possible increase in the degree of mineralization of bone are required.

Intrinsic mechanical properties of trabecular calcaneus determined by finite-element models using 3D synchrotron microtomography.

To determine intrinsic mechanical properties (elastic and failure) of trabecular calcaneus bone, chosen as a good predictor of hip fracture, we looked for the influence of image's size on a numerical simulation. One cubic sample of cancellous bone (9 x 9 x 9 mm(3)) was removed from the body of the calcaneus (6 females, 6 males, 79+/-9 yr). These samples were tested under compressive loading. Before compressive testing, these samples were imaged at 10.13 microm resolution using a 3D microcomputed tomography (muCT) (ESRF, France). The muCT images were converted to finite-element models. Depending on the bone density values (BV/TV), we compared two different finite element models: a linear hexahedral and a linear beam finite element models. Apparent experimental Young's modulus (E(app)(exp)) and maximum apparent experimental compressive stress (sigma(max)(exp)) were significantly correlated with bone density obtained by Archimedes's test (E(app)(exp)=236+/-231 MPa [19-742 MPa], sigma(max)(exp)=2.61+/-1.97 MPa [0.28-5.81 MPa], r>0.80, p<0.001). Under threshold at 40 microm, the size of the numerical samples (5.18(3) and 6.68(3)mm(3)) seems to be an important parameter on the accuracy of the results. The numerical trabecular Young's modulus was widely higher (E(trabecular)(num)=34,182+/-22,830 MPa [9700-87,211 MPa]) for the larger numerical samples and high BV/TV than those found classically by other techniques (4700-15,000 MPa). For rod-like bone samples (BV/TV<12%, n=7), Young's modulus, using linear beam element (E(trabecular)(num-skeleton): 10,305+/-5500 MPa), were closer to the Young's modulus found by other techniques. Those results show the limitation of hexahedral finite elements at 40 microm, mostly used, for thin trabecular structures.

Fluorotoxic metabolic bone disease: an osteo-renal syndrome caused by excess fluoride ingestion in the tropics.

BACKGROUND: There is scant data available on the pathogenetic mechanisms of varied clinical presentation of bone disease in patients with excess fluoride ingestion in the Indian subcontinent. The present study is comprehensive and state of the art, incorporating all essential elements of bone mineral metabolism in patients with excess fluoride ingestion. METHODS: We studied 24 patients (age 31 +/- 16 years) with fluorotoxic metabolic bone disease (FMBD) for their clinical, radiological and biochemical parameters like serum calcium, phosphorous, alkaline phosphatase (SAP), 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, and parathyroid hormone levels, nephrologic parameters that assess renal handling of calcium and phosphorous and skeletal dynamics as revealed by bone histomorphometry. FINDINGS: Major clinical manifestations were bone pain (79%), Tetany (12.5%) and dental mottling (38%). Radiological findings included osteosclerosis (96%), pseudofracture and ligamentous calcification (50%). These patients manifested hypocalcemia and raised SAP with normal serum phosphorus. There was a positive correlation between serum creatinine and phosphorous excretion index (PEI) and a negative correlation between declining endogenous creatinine clearance (Cr.Cl) and increasing renal loss of calcium and phosphorus as indicated by increased calcium to creatinine ratio and PEI. Bone histomorphometry revealed impairment of primary mineralization with hypomineralized lacunae, interstitial mineralization defects and very thick and extended osteoid seams. Autopsy findings in a patient who died of azotemia showed tubular atrophy with secondary glomerular changes. INTERPRETATION: Fluoride intoxication plays an important role in the pathogenesis of the unique osteo-renal syndrome.

[Phototype, vitamin D status and bone mineral density among women at risk of osteoporosis]. / Phototype, statut en vitamine D et densité minérale osseuse chez des femmes à risque d'ostéoporose.

PURPOSE: The aim of this study was to test the influence of phototype and vitamin D status feature on the bone mineral density (BMD) of the femoral neck in a group of middle-aged women considered at risk of osteoporosis (low levels of vitamin D [25(OH)D3<78 nmol/L] and hyperparathyroidism [parathormone level>36 pg/mL]). METHODS: This two-step study was conducted on 122 French women enrolled in the SUVIMAX (supplémentation en vitamines et minéraux antioxydants: antioxidant vitamin and mineral supplementation) cohort. The impact of various variables on BMD, including age, body mass index (BMI), vitamin D status, alcohol intake, sun exposure intensity and phototype was investigated using regression models. RESULTS: No statistical link was found between BMD and the variables documenting vitamin D status and parathormone levels, nor phototype. Nevertheless, fair phototypes tended to be associated with lower BMD values. However, BMD decreased with age and increased with BMI and physical activity level. CONCLUSIONS: Whatever their phototype, adult women concerned about precarious vitamin D status should undergo a vitamin D supplementation in combination with an adequate calcium intake all year long and a proper sun protection. Moreover, a physical activity maintenance should provide an additional benefit for prevention of osteoporosis.

Inhibition by diphosphonates of bone resorption induced by the Walker tumor of the rat.

An animal model is described to test the effect of diphosphonates, which are powerful antiosteolytic agents, against bone tumors. This model consists of injecting Walker tumor cells into one iliac artery of a series of rats while the contralateral artery is clamped during the injection, and waiting 7 days to obtain a significant destruction of the femur and tibia of the rats. In most of the animals, after this delay, extensive lesions are observed macroscopically by X-ray and histologically. The parenteral administration of three diphosphonates, dichloromethylene diphosphonate, ethanehydroxydiphosphonate , and aminopropanediphosphonate , at 16 and 160 mumol/kg/day, protects the bones by decreasing the extent of osteolysis. This protective effect is seen both in the tumor-injected leg and in the contralateral leg and is significant when compared to nontreated animals. The most active of the drugs was dichloromethylene-diphosphonate; ethanehydroxydiphosphonate and aminopropanediphosphonate were less active, especially when given at the higher dosage. All diphosphonates produce a marked decrease of the number of osteoclasts; ethanehydroxydiphosphonate at the higher dosage, induced a large increase of nonmineralized bone. These results are discussed in light of recent clinical work, showing that this animal model is a useful tool to test the effect of new drugs against osteolysis of cancer.

Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study.

BACKGROUND: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. METHODS: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. FINDINGS: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. CONCLUSION: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.

Quantitative ultrasound parameters as well as bone mineral density are better predictors of trochanteric than cervical hip fractures in elderly women. Results from the EPIDOS study.

RATIONALE: Hip fractures can be separated into cervical and trochanteric fractures. Trochanteric fractures have been associated with up to twice the short-term mortality of cervical fractures in the elderly. There is also evidence suggesting that the mechanisms are different. Evidence from the literature remains limited on the predictive power of bone mineral density (BMD) and quantitative ultrasounds (QUS) for both types of hip fractures. METHODS: 5703 elderly women aged 75 years or more, who were recruited from the voting lists in the EPIDOS study, and had baseline calcaneal ultrasounds (QUS) and DXA measurements at the hip and the whole body, were analyzed in this paper. Among those, 192 hip fractures occurred during an average follow-up of 4 years, 108 cervical and 84 trochanteric fractures. RESULTS: Femoral neck, trochanteric and whole body BMD were able to predict trochanteric hip fracture (RR's and 95% CI were, respectively, 3.2 (2.4-4.2); 4.8 (3.5-6.6); and 2.8 (2.2-3.6)) more accurately than cervical fractures (respectively, 2.1 (1.7-2.7); 2.3 (1.8-3.0); 1.2 (1.0-1.6)). All ultrasound parameters, SOS, BUA, and stiffness index (SI) were significant predictors of trochanteric (RR's respectively 3.0 (2.2-4.1), 2.5(2.0-3.1), and 3.5(2.6-4.7)) but not cervical fractures. After adjustment for femoral neck or trochanteric BMD ultrasound parameters were still significant predictors of trochanteric fracture, and stiffness tended to be a better predictor of trochanteric fractures than either BUA or SOS with a relative risk of 2.25 (1.6-3.1). CONCLUSIONS: A significant decrease of all bone measurements, BMD and QUS, was highly predictive of trochanteric fractures, whereas a decrease of femoral neck and trochanteric BMD were only associated with a slight increase in cervical fracture risk and a low total body BMD or QUS parameters were not significant predictors of cervical fractures. In women who sustained a hip fracture, the decrease of BMD and QUS values increases the risk of trochanteric fracture as compared to cervical fracture. Trochanteric fractures were mostly a consequence of a generalized low BMD and QUS, whereas other parameters might be involved in cervical fractures.

Relationship between compressive properties of human os calcis cancellous bone and microarchitecture assessed from 2D and 3D synchrotron microtomography.

The aim of this study was to determine the contribution of 2D and 3D microarchitectural characteristics in the assessment of the mechanical strength of os calcis cancellous bone. A sample of cancellous bone was removed in a medio-lateral direction from the posterior body of calcaneus, taken at autopsy in 17 subjects aged 61-91 years. The sample was first used for the assessment of morphological parameters from 2D morphometry and 3D synchrotron microtomography (microCT) (spatial resolution=10 microm). The 2D morphometry was obtained from three slices extracted from the 3D microCT images. Very good concordance was shown between 3D microCT slices and the corresponding physical histologic slices. In 2D, the standard histomorphometric parameters, fractal dimension, mean intercept length, and connectivity were computed. In 3D, histomorphometric parameters were computed using both the 3D mean intercept length method and model-independent techniques. The 3D fractal dimension and the 3D connectivity, assessed by Euler density, were also evaluated. The cubic samples were subjected to elastic compressive tests in three orthogonal directions (X, Y, Z) close to the main natural trabecular network directions. A test was performed until collapse of trabecular network in the main direction (Z). The mechanical properties were significantly correlated to most morphological parameters resulting from 2D and 3D analysis. In 2D, the correlation between the mechanical strength and bone volume/tissue volume was not significantly improved by adding structural parameters or connectivity parameter (nodes number/tissue volume). In 3D, one architectural parameter (the trabecular thickness, Tb.Th) permitted to improve the estimation of the compressive strength from the bone volume/tissue volume alone. However, this improvement was minor since the correlation with the BV/TV alone was high (r=0.96). In conclusion, which is in agreement with the statistic's rules, we found, in this study, that the determination of the os calcis bone compressive strength using the 3D bone volume fraction cannot be improved by adding 3D architectural parameters.

Bone loss in hypothyroidism with hormone replacement. A histomorphometric study.

To determine the influences of hormone replacement on bone tissue in primary hypothyroidism, a histomorphometric study on undecalcified transiliac bone specimens was performed before treatment in ten patients, during the first month of treatment in 16 patients, and after more than six months of treatment in 15 patients. There were no obvious clinical or biologic signs of excessive replacement therapy. Before treatment, trabecular resorption surfaces were lower and bone cortical thickness was increased. From as early as the first month of treatment, trabecular resorption surfaces and cortical porosity were higher than normal but cortical thickness was still increased. After more than six months of treatment there was a significant loss of trabecular (decreased trabecular bone volume) and cortical (normal mean cortical width; increased porosity) bone with hyperremodeling (increased trabecular resorption surfaces and trabecular osteoid surfaces). This osteoporosis is similar to that observed in hyperthyroidism.

X-ray microanalysis of fluoride distribution in microfracture calluses in cancellous iliac bone from osteoporotic patients treated with fluoride and untreated.

Fluoride is able to augment cancellous bone mass in vertebral osteoporosis but is responsible for osteoarticular side effects in which microfractures are thought to be involved. During healing of these microfractures, a callus is formed all around the cancellous fracture line. Our hypothesis is that in fluoride-treated osteoporotic patients, calluses are bone sites where fluoride is focally deposited at a high concentration, and this could induce a local defect of calcification with a poor healing of microfractures. Our aim was to validate this hypothesis on several calluses following microfractures in undecalcified iliac cancellous bone from six women with osteoporosis (four fluoride treated and two untreated). Histologically normal iliac cancellous bone tissue, taken from a subject having neither fluoride treatment nor microfracture, was also examined. Selected areas, including new woven bone (calluses) and old lamellar bone, were carbon-coated and analyzed using an electron microprobe. Fluoride K alpha and calcium K alpha radiations were detected with wavelength and energy-dispersive spectrometers, respectively. In old lamellar bone at a distance from microfractures, the fluoride level was similar in normal and untreated osteoporotic patients but was slightly increased in treated osteoporotic patients. In untreated osteoporotic patients, the fluoride level was slightly higher (about 1.2 times) at the site of microfractures (lamellar and woven bone) than in lamellar bone far from such fractures, but fluoride was homogeneously distributed in lamellar and woven bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteopenia and bone-remodeling abnormalities in warfarin-treated lambs.

The physiologic role of osteocalcin (OC), a vitamin K-dependent protein specific to bone, remains elusive. It has been shown that rats maintained on chronic treatment with vitamin K1 and its antagonist warfarin exhibit a marked decrease in bone osteocalcin because noncarboxylated osteocalcin does not bind to bone hydroxyapatite. To assess the role of OC in bone remodeling, we applied the warfarin model to growing lambs. We analyzed the bone changes after 3 months of concurrent warfarin and vitamin K1 treatment. Four groups of four lambs were constituted at birth and received daily a saline solution (control group, CT), 4 mg/kd/day of vitamin K1 (vitamin K group), 4 mg/kg/day of vitamin K1 + 75 or 150 mg/kg/day of warfarin (W75 and W150 group, respectively). In warfarin-treated animals, bone osteocalcin levels were decreased, both in the metaphysis (9% compared to controls) and the diaphysis (30% compared to controls) of the metacarpals. The fraction of noncarboxylated osteocalcin measured every month in the serum was significantly higher in warfarin-treated lambs than in controls at each timing point (37.6 +/- 2.6% in W75 and 48.7 +/- 5.2% in W150 versus 14.4 +/- 3.8% in controls at 3 months). Compared to non-warfarin-treated animals (NW), the main histomorphometric parameters measured on the iliac crest after tetracycline double labeling were significantly reduced in the warfarin-treated lambs: 12.2 +/- 5.2 versus 18.6 +/- 4.7% in NW (p < 0.03) for the cancellous bone area, which reflects the trabecular bone density; 14.7 +/- 6.1 versus 21.0 +/- 3.6% in NW (p < 0.03) for the eroded perimeter, and 0.315 +/- 0.064 versus 0.561 +/- 0.23 microns 3/microns 2/day in NW (p < 0.02) for the tetracycline-based bone formation rate. In conclusion, the depletion of osteocalcin in the bone of lambs induced within 3 months a marked osteopenia that resulted from a decrease in resorption and a more pronounced decrease in bone formation. Our data suggest that the presence of osteocalcin, the major gla-containing protein of bone, may be important for the maintenance of a normal bone mass and remodeling of trabecular bone.

Fluoride content in human iliac bone: results in controls, patients with fluorosis, and osteoporotic patients treated with fluoride.

The major part of fluoride ingested is fixed on calcified tissues, mainly in bone tissue, and then is progressively but slowly recycled during bone remodeling. Thus, the measurement of bone fluoride content allows the determination of the extent of bone fluoride retention, and this parameter constitutes a useful complement to bone histology for the diagnosis of skeletal fluorosis and could also be used for the management of fluoride treatment of osteoporosis. A simple method is described to measure the fluoride content in calcined human iliac bone samples. Bone ashes were diluted in perchloric acid, and the measurement of the bone fluoride content was performed using a specific ion electrode combined with a reference electrode. Reference values are given for bone tissue from 76 control subjects (0.08 +/- 0.05% of bone ash), from two groups of 117 and 102 untreated osteoporotic patients (0.05 +/- 0.03% and 0.08 +/- 0.05%, respectively), from 166 sodium fluoride-treated osteoporotic patients (mean bone fluoride content varying from 0.24 to 0.67%, depending on the duration of therapy), and from 96 patients showing typical skeletal fluorosis (mean bone fluoride content varying from 0.56 to 1.33%, depending on the etiology of fluorosis and the relationship with the amount of fluoride ingested as well as with the duration of fluoride exposure). During a prolonged exposure of adult bone tissue to fluoride, the early bone fluoride uptake is variable and depends on the remodeling activity; then it increases rapidly before becoming more or less stable at a maximum level.

Long-term effects of intravenous pamidronate in fibrous dysplasia of bone.

Fibrous dysplasia of bone (FD) is a rare disorder characterized by proliferation of fibrous tissue in bone marrow leading to osteolytic lesions. It causes bone pain and fractures. To date the only treatment is orthopedic. Histological and biochemical similarities between FD and Paget's bone disease related to increased osteoclastic resorption led us to propose treatment with the bisphosphonate pamidronate. The aim of the study was to assess the long-term effects of intravenous pamidronate in FD. In this open label phase III study, 20 patients with FD (11 males and 9 females; mean age 31 years) received courses of 180 mg of intravenous pamidronate every 6 months (60 mg/day during 3 days by infusion). The mean duration of follow-up was 39 months (range 18-64). Severity of bone pain, number of painful skeletal sites per patient, X-rays of all involved areas, serum alkaline phosphatase, fasting urinary hydroxyproline, and urinary type I collagen C-telopeptide were assessed every 6 months. The severity of bone pain and the number of painful sites appeared to be significantly reduced. All biochemical markers of bone remodeling were substantially lowered. We observed a radiographic response in nine patients with refilling of osteolytic lesions. A mineralization defect proven by bone biopsy was observed in one case. Four patients sustained bone stress lines, but no fracture occurred. We suggest that intravenous pamidronate alleviates bone pain, reduces the rate of bone turnover assessed by biochemical markers, and improves radiological lesions of FD. Few side effects were observed.