Israel Medical Association Journal

Background: Evidence suggests that prolonged bisphosphonate (BP) treatment predisposes to atypical fractures (AF), but the etiology has yet to be determined. Addressing causality begins with case identification, which requires radiological adjudication. However, many trials based their case findings on coded diagnoses. 

Objectives: To investigate the feasibility of case findings by the coding system and the reproducibility of radiological evaluations in two hospitals in Israel, and to compare BP exposure of AF patients to a control group with typical (intertrochanteric of femoral neck) fractures. 

Methods: Diagnostic databases from 2007–2010 were reviewed and admission X-rays of patients were examined in two steps by two radiologists. Fractures were classified as atypical or not atypical according to published criteria. A 2:1 control group was created. Ambulatory drug acquisition was reviewed. 

Results: Of the 198 patients who fulfilled the search criteria, 38 were classified by initial radiological opinion as AF. Subsequent radiological opinion judged 16 as not atypical. Of the AF patients, 80% were exposed to BP. Of those, 81% continued to receive BP treatment for 2.4 years after AF. Only one AF patient was discharged with suspected AF diagnosis. In the control group, 27% were exposed to BP prior to fracture (P < 0.001). 

Conclusions: Thorough radiological revision is mandatory for proper classification of AF, and even when performed there is significant inconsistency in interpretation. Conclusions drawn from trials based solely on coded diagnoses lead to significant bias. BP exposure was significantly higher in the AF group. Caregiver unawareness of AF leads to improper management. 

 

 Background: Vitamin D status is not evaluated routinely in cancer patients with bone metastasis who are treated with bisphosphonates.

Objectives: To assess the effect of vitamin D status on risk of hypocalcemia and quality of life in these patients.

Methods: We performed laboratory tests for routine serum biochemistry, 25(OH)D, plasma parathyroid hormone (PTH) and bone turnover markers (CTX, P1NP) in 54 patients aged 57.5 ± 13 years treated with intravenous bisphosphonates.

Results: Most of the patients (n=44, 77.8%) did not receive calcium and vitamin D supplementation. Their mean serum 25(OH)D levels (12.83 ± 6.86 ng/ml) correlated with vitamin D daily intake (P = 0.002). In 53 patients (98.1%) 25(OH)D levels were suboptimal (< 30 ng/ml). Albumin-corrected calcium levels correlated with plasma PTH (P = 0.001). No correlation was observed between daily calcium intake and serum calcium (P = 0.45). Hypocalcemia was observed in one patient. Mean plasma PTH was 88.5 ± 65 ng/L. Plasma PTH correlated negatively with 25(OH)D serum levels (P = 0.003) and positively with P1NP (P = 0.004). Albumin-corrected calcium correlated negatively with P1NP (mean 126.9 ± 191 ng/ml) but not with CTX levels (mean 0.265 ± 0.1 ng/ml) (P < 0.001). There was no correlation among quality of life parameters, yearly sun exposure and 25(OH)D levels (P = 0.99).

Conclusions: Vitamin D deficiency is frequent in oncology patients with bone metastasis treated with bisphosphonates and might increase bone damage. Our results indicate a minor risk for the development of severe hypocalcemia in vitamin D-deficient patients receiving bisphosphonate therapy. Although vitamin D deficiency might have some effect on the quality of life in these patients, it was not proven significant.
 

Background: Hip fracture rates are increasing worldwide, and the risk for a second hip fracture is high. The decision to administer antiresorptive treatment is based mainly on bone mineral density and/or a history of previous osteoporotic fractures.

Objectives: To evaluate the contribution of BMD[1], previous fractures, clinical and laboratory parameters to hip fracture risk assessment.

Methods: The study population included 113 consecutive hip fracture patients, aged 72.5 ± 9.4 years, discharged from the Department of Orthopedic Surgery113 consecutive patients, 87 women and 26 men, aged 50-90 years, mean ag. BMD was assessed at the lumbar spine, femoral neck and total hip. The results were expressed in standard deviation scores as T-scores – compared to young adults and Z-scores – compared to age-matched controls. Plasma or serum levels of parathyroid hormone, 25-hydroxyvitamin 3 and urinary deoxypyridinoline cross-links were evaluated.

Results: We observed T-scores ≤-2.5 in 43 patients (45.3%) at the lumbar spine, in 47 (52.2%) at the femoral neck and in 33 (38%) at the total hip. Twenty-eight patients (29.5%) had neither low BMD nor previous osteoporotic fractures. Using a T-score cutoff point of (-1.5) at any measurement site would put 25 (89%) of these patients into the high fracture risk group. Mean DPD level was 15.9 ± 5.8 ng/mg (normal 4–7.3 ng/mg creatinine). Vitamin D inadequacy was observed in 99% of patients.

Conclusions: Using current criteria, about one-third of elderly hip fracture patients might not have been diagnosed as being at risk. Lowering the BMD cutoff point for patients with additional risk factors may improve risk prediction yield.

Background: Chlorpromazine is a dopamine-receptor antagonist antipsychotic agent. Because of its strong alpha-blocking and sedative actions, it has also been used as emergency therapy for extreme arterial hypertension. Published reports to date have included very small numbers of patients (i.e., 5–30).

Objectives: To analyze data on almost 500 patients who received intravenous chlorpromazine for the emergency treatment of uncontrolled symptomatic hypertension in the pre-hospital setting.

Methods: We reviewed data from 496 consecutive patients who received intravenous chlorpromazine as emergency therapy for uncontrolled symptomatic hypertension. Chlorpromazine was injected intravenously. The dose was 1 mg every 2–5 minutes until the systolic pressure was -<140 mmHg and the diastolic pressure -<100 mmHg with alleviation of symptoms.

Results: The mean dose of chlorpromazine administered was 4.5 +- 5 mg (range 1–50 mg). Only 33 patients (7%) required >10 mg. Chlorpromazine reduced the systolic blood pressure from 222.82 +- 26.31 to 164.93 +- 22.66 mmHg (P < 0.001) and the diastolic blood pressure from 113.5 +- 16.63 to 85.83 +- 11.61 mmHg (P < 0.001). The sinus rate decreased from 97.9 +- 23.5 to 92.2 +- 19.7 beats per minute (P < 0.001). These results were achieved within the first 37 +- 11 minutes.

Conclusions: Intravenous chlorpromazine is safe and effective when used as emergency treatment for uncontrolled symptomatic hypertension.

Objective: To evaluate the contribution of the sestamibi-SPECT (MIBI) localization, cervical ultrasonography, and intraoperative rapid turbo intact parathormone assay in minimal invasive parathyroidectomy.

Methods: Between August 1999 and March 2004, 146 consecutive hyperthyroid patients were treated using the MIBI and ultrasound for preoperative localization and iPTH[1] measurements for intraoperative assessment.

Results: Parathyroid adenoma was detected in 106 patients, primary hyperplasia in 16, secondary hyperplasia in 16, tertiary hyperplasia in 5 and parathyroid carcinoma in 1 patient. Minimal invasive exploration of the neck was performed in 84 of the 106 patients (79.2%) with an adenoma, and in 17 of them this procedure was performed under local cervical block anesthesia in awake patients. Adenoma was correctly diagnosed by MIBI scan in 74% of the patients, and by ultrasound in 61%. The addition of ultrasonography to MIBI increased the accuracy of adenoma detection to 83%. In 2 of the 146 patients (1.4%) iPTH could not be significantly reduced during the initial surgical procedure. Minimal invasive surgery with minimal morbidity, and avoiding bilateral neck exploration, was achieved in 79.2% of patients with a primary solitary adenoma.

Background: The treatment of osteoporosis among postmenopausal women represents a major public health challenge since long-term therapy is needed to prevent fractures and chronic disability.

Objectives: To assess compliance with osteoporosis drug therapy among Israeli postmenopausal women treated with either a bisphosphonate (alendronate) or a selective estrogen receptor modulator (raloxifene); to identify factors affecting compliance among these patients; and to compare adherence to the treatment in these two groups.

Methods: Our study included 178 consecutive patients aged 67.41 ± 8.52 years who were treated for osteoporosis with alendronate or raloxifene in the Metabolic Bone Diseases Unit. All the patients received supplement with calcium carbonate 1,500 mg and 600 IU vitamin D daily. Compliance was assessed at a clinic visit 6 months after starting therapy.

Results: The dropout rate was 23% (41 patients): 20 patients (31%) in the raloxifene group and 21 (18%) in the alendronate group (P = 0.0041). The main reasons for dropout were side effects and/or non-compliance, 16 and 24 patients (39% and 58.53%), respectively. The most frequent side effect was abdominal pain in 9 patients (42.8%) who discontinued alendronate use. The reasons for non-compliance were a fear of side effects and high drug price in 6 (30%) and 4 (20%) patients respectively in the raloxifene group, and inconvenience caused by medication use in 3 (14.3%) patients in the alendronate group. Logistic regression analysis of factors that may influence compliance included age, previous fractures, family history of osteoporosis, bone density T-score less than -2.5, and presence and number of concomitant diseases. Age was the only statistically significant parameter in this model: 67.8 ± 8.8 in non-compliant versus 64.11 ± 7.4 in compliant patients (P = 0.029).

Conclusion: At least 20% of the patients discontinued chronic treatment for osteoporosis during the initial 6 months of therapy. The main reasons were gastrointestinal side effects in the alendronate group, and fear of side effects and high drug price in the raloxifene group. Older age was the only statistically significant factor influencing compliance.

Background: Genetic factors have been shown to play a major role in the development of peak bone mass, with hereditability accounting for about 50-85% of the variance in bone mass. Numerous candidate genes were proposed to be involved in osteoporosis, but the precise genes and their relative contribution remain unknown.

Objectives: To gain insight into the genetic basis of idiopathic low bone mineral density in Israeli patients by analyzing the impact of two candidate genes: polymorphism of the vitamin D receptor gene and polymorphism A986s in the calcium-sensing receptor gene.

Methods: We analyzed 86 Jewish Israeli patients with LBMD[1]: 38 premenopausal women and 48 men, and compared the allelic pattern distribution with that of the general population (126 men and 112 women). Genotyping of the VDR[2] gene was performed in three polymorphic sites using restriction enzymes, and allelic analysis of A986s polymorphism in the CaSR[3] gene was performed using the denaturing gradient gel electrophoresis technique.  

Reaults: In LBMD women the distributions of VDR alleres in Apal polymorphism were AA=7/28, Aa=16/28 and aa=5/28; in TaqI polymorphism TT=10/31, Tt=16/31 and tt=5/31; and in BsmI polymorphism BB=7/32, Bb=14/32 and 11/32. In LBMD men the distributions were AA=17/39, Aa=21/39 and aa=1/39; in TaqI polymorphism TT=12/42, Tt=23/42 and tt=7/42; and in BsmI polymorphism BB=12/41 Bb=18/41 and bb=11/41. The distributions of all these polymorphisms in the control groups were not significantly different. Adjusting for the independent age and gender parameters confirmed that these three polymorphisms of the VDR gene did not have a significant effect on bone mineral density. Thirty percent (24/79) of LBMD patients of either sex displayed heterozygosity of the CaSR A986s polymorphism, compared with 40 of 203 controls (19.7%) (P=0.059). Adjusting for age and gender in these patients revealed a significant difference in the femoral neck BMD[4] between homozygotes and heterozygotes (P=0.002). The age at menarche of the LBMD women was found to predict 61% of the variance of femoral neck BMD.

Conclusions: In Israeli Jewish men and premenopausal women VDR gene alleles do not seem to be associated with lower lumbar spine or femoral neck BMD. A trend towards heterozygosity for a CaSR polymorphism missense mutation was noted in the LBMD patients. Age at menarche in the LBMD women was found to be an important predictor of BMD. A significant difference was found between LBMD women and healthy control women towards heterozygosity for a CaSR polymorphism, as well between homozygotes and heterozygotes for a CaSR polymorphism in BMD. The significance of these findings and their applicability to a larger population awaits further studies.

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