Cortical osteoclasts are less sensitive to etidronate than trabecular osteoclasts

Acute osteoporosis after spinal cord injury is related to an early increase in osteoclastic resorption. Healthy subjects subjected to bed rest similarly increase their osteoclast number in trabecular bone. Bisphosphonates possess a highly antiosteoclastic activity. The effects of a 120 day bed rest period, with or without etidronate therapy on cortical bone were measured in 15 subjects. Cortical thickness and cortical porosity were measured on transiliac bone biopsies taken before and after the bed rest period. Osteoclasts were detected histochemically and were counted with a semiautomatic image analyzer. Cortical thickness, cortical porosity, and cortical osteoclast number were not significantly modified in subjects submitted to bed rest alone. In the etidronate-treated patients, cortical bone mass parameters were also found to be unaffected, but the most striking feature was that the osteoclast number was unchanged. Trabecular osteoclasts, on the contrary, were increased in the untreated subjects (+95.2%) but decreased in the treated subjects (-78%). Bone cells may have heterogeneous responses according to their trabecular or cortical location. Cortical osteoclasts seem to be unaffected by etidronate therapy.     

The reversibility of disuse osteoporosis. Fluoride treatment and bone strength

The biomechanical strength of femur of adult rats was tested after immobilization for 9 weeks and remobilization for 12 weeks of 1 hind leg. Some rats were also given a fluoride supplement of 200 ppm in the drinking water. As reflected in the ultimate torque and stiffness there was a decrease in bone strength due to immobilization. After 12 weeks of remobilization the stiffness remained lower than in normal animals of the same age. Fluoride supplement partially counteracted the effect of immobilization but after the remobilization period no positive effect of the fluoride supplement was observed. Remobilization per se is of much more significance than fluoride in restoration of bone strength.     

Genetically linked site-specificity of disuse osteoporosis.

The genetic influence on bone loss in response to mechanical unloading was investigated within diaphyseal and distal femoral regions in three genetically distinct strains of mice. One mouse strain failed to lose bone after removal of function, whereas osteopenia was evident in multiple regions of the remaining two strains but in different areas of the bone. INTRODUCTION: It is well recognized that susceptibility to osteoporosis is, in large measure, determined by the genome, but whether this influence is systemic or site-specific is not yet known. Here, the extent to which genetic variations influence regional bone loss caused by disuse was studied in the femora of adult female mice from three inbred strains. MATERIALS AND METHODS: Adult C57BL/6J (B6), C3H/HeJ (C3H), and BALB/cByJ (BALB) mice were subjected to 15-21 days of disuse, achieved by hindlimb suspension, and six distinct anatomical regions of the femur were analyzed by high-resolution microCT. RESULTS AND CONCLUSIONS: In B6 mice, the amount of disuse stimulated bone loss was relatively uniform across all regions, with 20% loss of trabecular bone and 10% loss of cortical bone. The degree of bone loss in BALB mice varied greatly, ranging from 59% in the metaphysis to 3% in the proximal diaphysis. In this strain, the nonuniformity of bone loss was directly related to the nonuniform distribution of baseline bone morphology (r2 = 0.94). In direct contrast with BALB and B6, disuse failed to produce significant losses of bone in any of the analyzed regions of the C3H mice. Instead, these animals displayed a unique compensatory mechanism to disuse, where the large loss of calcified tissue from the endocortical surface (-24%) was compensated for by an expansion of the periosteal envelope (10%). These data indicate a strong, yet complex, genetic dependence of the site-specific regulation of bone remodeling in response to a powerful catabolic signal. Consequently, the skeletal region of interest and the genetic make-up of the individual may have to be considered interdependently when considering the pathogenesis of osteoporosis or the efficacy of an intervention to prevent or recover bone loss.     

Bisphosphonates in bone diseases other than osteoporosis

The range of bone diseases in which bisphosphonates are used has extended far beyond osteoporosis during the last few years. Bisphosphonate therapy is now so well validated as to be the reference standard in Paget's disease and in the prevention of bone complications related to malignant osteolysis. Promising preliminary findings warrant the use of bisphosphonates in conditions that are either rare (fibrous dysplasia) or severe (pediatric osteogenesis imperfecta). The third category of indications encompasses many conditions in which the limited available data do not warrant widespread use: examples include reflex sympathetic dystrophy syndrome, acute back pain after a vertebral crush fracture, and chronic inflammatory joint disease not treated by glucocorticoids.     

Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis

A potential side effect associated with bisphosphonates, a class of drugs used in the treatment of osteoporosis, Paget's disease and metastatic bone disease, is osteonecrosis of the jaw (ONJ). The incidence of ONJ in the general population is unknown; this rare condition also may occur in patients not receiving bisphosphonates. Case reports have discussed ONJ development in patients with multiple myeloma or metastatic breast cancer receiving bisphosphonates as palliation for bone metastases. These patients are also receiving chemotherapeutic agents that might impair the immune system and affect angiogenesis. The incidence or prevalence of ONJ in patients taking bisphosphonates for osteoporosis seems to be very rare. No causative relationship has been unequivocally demonstrated between ONJ and bisphosphonate therapy. A majority of ONJ occurs after tooth extraction. Furthermore, the underlying risk of developing ONJ may be increased in osteoporotic patients by comorbid diseases. Treatment for ONJ is generally conservative.     

Prolonged bisphosphonate release after treatment in women with osteoporosis. Relationship with bone turnover

Bisphosphonates (BP), especially alendronate and risedronate, are the drugs most commonly used for osteoporosis treatment, being incorporated into the skeleton where they inhibit bone resorption and are thereafter slowly released during bone turnover. However, there are few data on the release of BP in patients who have received treatment with these drugs for osteoporosis. This information is essential for evaluating the possibility of BP cyclic therapy in these patients and for controlling their long-term presence in bone tissue. This study evaluated the urinary excretion of alendronate and risedronate in patients treated with these drugs for osteoporosis and analysed its relationship with bone turnover, time of previous drug exposure and time of treatment discontinuation. We included 43 women (aged 65 ± 9.4 years) previously treated with alendronate (36) or risedronate (7) during a mean of 51 ± 3 and 53 ± 3 months, respectively, who had not been treated with other antiosteoporotic treatment and with a median time of discontinuation of 13.5 and 14 months, respectively. Both BP were detected in 24-hour urine by HPLC. In addition, bone formation (PINP) and resorption (NTx) markers were analysed. Both BP were also determined in a control group of women during treatment. Alendronate was detected in 41% of women previously treated with this drug whereas no patient previously treated with risedronate showed detectable urinary values. All control patients showed detectable values of both BP. In patients with detectable alendronate levels, the time of drug cessation was shorter than in patients with undetectable values (12 [6–19] versus 31 [7–72] months, p < 0.001). Alendronate was not detected in any patient 19 months after treatment cessation. Alendronate levels were inversely related to time of treatment discontinuation (r = − 0.403, p = 0.01) and the latter was directly related to NTx (r = 0.394, p = 0.02). No relationship was observed with age, length of drug exposure, renal function or weight.In conclusion, contrary to risedronate, which was not detected in patients after cessation of treatment, alendronate was frequently detected in women previously treated with this agent up to 19 months after discontinuation of therapy. The relationship between alendronate levels and both bone resorption and time of treatment cessation further indicates a residual effect of this drug in bone, despite treatment discontinuation.     

25 hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis

It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis.MethodsWe included 120 postmenopausal osteoporotic women (aged 68 ± 8 years) receiving BP (alendronate or risedronate) at their annual follow-up, performing complete anamnesis, including treatment adherence, use of vitamin D supplements, and previous falls and fractures during the last year. We analyzed the evolution of bone mineral density (BMD) during this period and serum PTH and 25 hydroxyvitamin D (25(OH)D) and urinary NTx levels. Patients were classified as inadequate responders to antiosteoporotic treatment based on BMD loss > 2% and/or the presence of fragility fractures during the last year.ResultsThirty percent of patients showed inadequate response to BP treatment, with significantly lower levels of 25(OH)D (22.4 ± 1.3 vs. 26.6 ± 0.3 ng/ml, p = 0.01), a higher frequency of 25(OH)D levels < 30 ng/ml (91% vs. 69%, p = 0.019) and higher urinary NTx values (42.2 ± 3.9 vs. 30.9 ± 2.3 nM/mM, p = 0.01). Patients with 25(OH)D > 30 ng/ml had a greater significant increase in lumbar BMD than women with values < 30 ng/ml (3.6% vs. 0.8%, p < 0.05). The probability of inadequate response was 4-fold higher in patients with 25(OH)D < 30 (OR, 4.42; 95% CI, 1.22–15.97, p = 0.02).ConclusionsInadequate response to BP treatment is frequent in postmenopausal women with osteoporosis as is vitamin D insufficiency, despite vitamin D supplementation. Maintenance of 25(OH)D levels > 30 ng/ml is especially indicated for adequate response to BP treatment.     

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Summary

Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8 % of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure.

Introduction

To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO).

Methods

We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥7.5 %, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥2 incident fragility fractures and/or a BMD decrease greater than the least significant change.

Results

Bisphosphonate treatment failure was observed in 25.8 % of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95 % CI 1.10–9.50, P?=?0.034) and baseline alkaline phosphatase total activity levels ≥66.5 U/L (OR 4.22, 95 % CI 1.48–12.01, P?=?0.007), regardless of age, number of falls, LS BMD, and baseline SDI.

Conclusions

The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.     

早期使用双膦酸盐预防糖尿病性骨质疏松的研究

目的对51例病史长短不一且合并骨量低下或已发生骨质疏松的2型糖尿病患者使用双膦酸盐静脉注射,并对注射双膦酸盐前后所测得骨密度的数据结果进行统计学分析,评价其疗效与病史长短之间的关系。方法 (1)选择标本并分组:选择51例病史长短不一且合并骨量低下或已发生骨质疏松的2型糖尿病患者,且保证其年龄、性别控制在50～80岁男性,或小于80岁的绝经女性,按照其糖尿病病史分为3组:A组(1～5年组),B组(6～10年组),C组(10年组);(2)利用双能X线骨密度仪检测各个患者注射唑来膦酸钠前后的Ward’s三角以及L1-L3椎体的骨密度;(3)运用方差分析方法分析糖尿病病史长短对双膦酸盐防治骨质疏松疗效的影响。结果 6～10年组与10年组之间的防治骨质疏松疗效差异无统计学意义;1～5年组防治骨质疏松疗效优于6～10年组以及10年组。结论早期使用双膦酸盐静脉注射进行预防糖尿病性骨质疏松可取得更好疗效。     

静脉注射双膦酸盐治疗更年期骨质疏松症疗效分析

目的 探讨双膦酸盐(艾本)治疗老年骨质疏松症的临床疗效。方法 选择60例更年期骨质疏松症患者随机分为对照组及实验组,实验组应用二膦酸盐2mg每三个月一次静滴,同时口服活性维生素D和钙剂,对照组给予平衡盐溶液每三个月一次,同时口服活性维生素D和钙剂。分别于治疗前和治疗后3个月、6个月、9个月、12个月进行骨密度测量。结果 治疗后3个月和6个月骨密度增加不明显,治疗9个月和12个月后骨密度显著升高,与对照组有显著性差异(P＜0.01)。结论 使用二膦酸盐治疗骨质疏松,能在一定程度上抑制骨丢失,增加骨密度,治疗骨质疏松,改善老年骨质疏松患者的生活质量。     

Long-term treatment of established osteoporosis with intranasal calcitonin

We examined the long-term effects of intranasal administration of salmon calcitonin on bone and calcium metabolism in women with established osteoporosis (forearm fracture). Over a period of 5 years, 14 women received discontinuous calcitonin (200 IU) plus calcium (500 mg) daily for 3 years or 4 years. To allow assessment of the optimum duration of therapy, patients in whom treatment had been for shorter intervals were also included. At the end of the first 2 years, a group receiving placebo had lost significantly more bone from their spines and forearms than the group receiving calcitonin in the first year (P<0.01). In the 14 women who completed a further 3 years on calcitonin, the bone mineral contents of the spines increased continually. Bone loss in the forearm was arrested for 1 year. Treatment lasting for about 2 years prevented bone loss in both areas. Treatment for 3 years resulted in net gains in spinal bone but no further benefits in relation to forearms. Biochemical parameters of bone turnover (serum alkaline phosphatase levels, plasma bone Gla protein levels, and fasting urinary hydroxy-proline/creatinine levels) exhibited similar declines irrespective of the duration of treatment. It is concluded that longterm intranasal treatment with calcitonin produced net gains in spinal bone and that optimum response in forearms was achieved using discontinuous therapy. The ratio between periods with and without treatment was between 1∶2 and 2∶3.     

Radiographic evidence of disuse osteoporosis in the monkey (M. nemestrina)

Summary Radiological techniques were utilized for monitoring progressive changes in compact bone in the tibia of monkeys during experimentally induced osteopenia. Bone mass loss in the tibia during restraint was evaluated from radiographs, from bone mineral analysis, and from images reconstructed from gamma ray computerized tomography. The losses during 6 months of restraint tended to occur predominantly in the proximal tibia and were characterized by subperiosteal bone loss, intracortical striations, and scalloped endosteal surfaces. Bone mineral content in the cross section of the tibia declined 17–21%. Tomography demonstrated endosteal widening and reduced mineral content per unit of thickness of cortical bone. In 6 months of recovery, the mineral content of the proximal tibia remained depressed. Effects of the dynamic environment on local-regional changes in various skeletal areas are discussed.     

Changes in urinary NTX levels in patients with primary osteoporosis undergoing long-term bisphosphonate treatment

BACKGROUND: Bisphosphonates, antiresorptive drugs, are widely used to treat osteoporosis patients. However, recent reports indicated that several osteoporosis patients who underwent long-term bisphosphonate therapy subsequently developed severe suppression of bone turnover. We investigated whether urinary crosslinked N-telopeptide of type I collagen (NTX), a bone resorption marker, in osteoporosis patients was highly suppressed during long-term treatment with alendronate or risedronate. METHODS: We investigated 87 primary osteoporosis outpatients who were treated with alendronate or risedronate for more than 2 years. All patients were women, with an average age of 72.6 years. Altogether, 49 patients were treated with alendronate and 38 with risedronate, and the average administration period was 3.5 years. We defined high suppression as NTX being reduced <9.3 nmol bone collagen equivalent/mmol.Cr and a 35% decrease from baseline. RESULTS: In total, 11 of 87 patients (12.6%) had high NTX suppression based on the above criteria. The incidences of high suppression of NTX at 1,2,3,and 4 years after starting the treatment were 0%, 1.1%, 11.9%, and 4.7%, respectively. The average age, bone mineral density, and NTX values at baseline and the administration period were not associated with high suppression of NTX during alendronate or risedronate treatment. Regarding suppression of NTX during long-term treatment, there was no significant difference between alendronate and risedronate. CONCLUSIONS: The results suggested that long-term treatment with bisphosphonates necessitates careful follow-up of the patients.     

Long-term results of cemented Charnley low-friction arthroplasty in patients aged less than 30 years

The results of cemented Charnley low-friction arthroplasty in patients aged less than 30 years are presented. Eighty-three arthroplasties were performed on 55 patients with an average age of 24.9 years (range, 17–29 years) and an average follow-up period of 240 months (20 years; range, 62–360 months). There were 2 nonfatal pulmonary emboli, 2 cases of deep sepsis, and 3 fractured femoral implants. Twenty-eight acetabular components migrated (34%), 25 have been revised (30%), and the average annual acetabular wear rate was 0.12 mm. Sixteen femoral implants subsided (19%), and fracture of the tip of the cement mantle occurred in 8 hips (10%). Nineteen femoral components (23%) were revised; femoral osteolysis was seen in 15 hips (18%) and changes in the calcar in 33 (38%). Acetabular component survivorship was 92% (95% confidence interval, 85–98%) at 10 years, 70% (60–81%) at 20 years, and 68% (57–79%) at 25 years, with the figures for the femoral implant being 93% (87–98%), 76% (66–86%), and 73% (62–85%), respectively.     

Long-term results of total correction of tetralogy of Fallot less than 2 years old

Between April 1972 and March 1979, eighteen total correction for tetralogy of Fallot less than 2 years old were performed with a mortality rate of 11.1%. The valved patch made of autologous pericardium was utilized for right ventricular outflow reconstruction in 12 of 16 survivors. Late (from 10 to 17 postoperative year) results of the all survivors were studied on functional and clinical status, hemodynamics and cardiac functions, and also, were compared with that of the patients above 2 years of age. All of them were in NYHA class I with no physical exercise limitation. Chest X-ray showed nearly normal CTR of 51.7%. ECG showed complete or incomplete RBBB in 14 patients and LAD in 3 of them, whereas no ventricular arrhythmia. Cardiac catheterization and cineangiography revealed that they had quite satisfactory hemodynamics and cardiac functions despite their moderate pulmonary regurgitation. In comparison with the older patient group, this younger one had a tendency to take superior results in all parameters of cardiac functions and clinical status. These excellent long term results seem to come from their young and less degenerative myocardium at the time of surgery.