Clarita V. Odvina

Unusual mid‐shaft fractures during long‐term bisphosphonate therapy

Background  Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although existing evidence supports a good safety profile, there is concern that chronic administration of these agents could result in severe suppression of bone turnover with increased risk of nonvertebral fractures.

Prevention of Stone Formation and Bone Loss In Absorptive Hypercalciuria by Combined Dietary and Pharmacological Interventions

PURPOSE We determined whether dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate treatment, would prevent stone formation and avert bone loss in 18 men and 10 women with type I absorptive hypercalciuria. MATERIALS AND METHODS Patients were treated with thiazide (20) or indapamide (8) and potassium citrate (average dose 35 mEq. daily) for 1 to 11 years (mean 3.7) while maintained on low calcium oxalate diet. Serum and urinary chemistry studies and bone mineral density were measured at baseline and at the end of treatment. New stones formed were quantitated during 3 years before and during treatment. RESULTS During treatment urinary calcium significantly decreased (346 +/- 85 to 248 +/- 79 mg. daily, p <0.001) but urinary oxalate did not change. Urinary pH and citrate significantly increased, and urinary saturation of calcium oxalate significantly decreased by 46%. Stone formation rate decreased significantly from 2.94 to 0.05 per year (p <0.001). L2-L4 bone mineral density increased significantly by 5.7% compared to normal peak value, and by 7.1% compared with normal age and gender matched value. Femoral neck bone mineral density also increased significantly. CONCLUSIONS Dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate, satisfactorily controlled hypercalciuria, prevented the secondary increase in urinary oxalate, reduced urinary saturation of calcium oxalate, virtually eliminated recurrent stone formation, and increased bone density of the spine and femoral neck. Thus, this dietary pharmacological program controlled stone formation as well as bone loss that often accompany type 1 absorptive hypercalciuria.

BISPHOSPHONATE-INDUCED HYPOCALCEMIA: REPORT OF 3 CASES AND REVIEW OF LITERATURE

OBJECTIVE To report 3 cases of bisphosphonate-induced hypocalcemia and review the relevant literature. METHODS We present the clinical and laboratory findings in 3 cases of bisphosphonate-induced hypocalcemia, and discuss the pathophysiologic mechanisms and the pertinent literature. RESULTS In our first patient (case 1), symptomatic hypocalcemia developed after intravenous administration of pamidronate for management of multiple myeloma. He had vitamin D insufficiency and impaired renal function at the time of pamidronate therapy. Our second patient (case 2) presented with symptomatic hypocalcemia 12 weeks after initiation of alendronate therapy for osteoporosis. Her serum 25-hydroxyvitamin D level was low (3 ng/mL), attributable to a combination of poor vitamin D intake, limited exposure to sunlight, use of phenytoin, and previous intestinal resections. In our third patient (case 3), hypocalcemia developed on 2 different occasions, each episode occurring after intravenous administration of pamidronate for hypercalcemia of malignancy. All 3 patients had underlying conditions that impaired the homeostatic response to bisphosphonates and contributed to the severe hypocalcemia. Review of published reports on symptomatic bisphosphonate-induced hypocalcemia disclosed that hypocalcemia develops in patients with unrecognized hypoparathyroidism, impaired renal function, or vitamin D deficiency. Overall, the rate of the development of hypocalcemia was related to the potency of the bisphosphonate administered. CONCLUSION The increasing use of bisphosphonates and the introduction of more potent agents impose a considerable risk for bisphosphonate-induced hypocalcemia in a substantial number of patients. Greater awareness of this complication, a better understanding of the underlying mechanisms, and proper assessment of patients in whom bisphosphonate therapy is contemplated should reduce the frequency of occurrence of this potentially life-threatening complication.

Mechanical property and tissue mineral density differences among severely suppressed bone turnover (SSBT) patients, osteoporotic patients, and normal subjects

Pathogenesis of atypical fractures in patients on long term bisphosphonate therapy is poorly understood, and the type, the manner in which they occur and the fracture sites are quite different from the usual osteoporotic fractures. We hypothesized that the tissue-level mechanical properties and mean degree of mineralization of the iliac bone would differ among 1) patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy, 2) age-matched, treatment-naïve osteoporotic patients with vertebral fracture, 3) age-matched normals and 4) young normals. Large differences in tissue-level mechanical properties and/or mineralization among these groups could help explain the underlying mechanism(s) for the occurrence of typical osteoporotic and the atypical femoral shaft fractures. Elastic modulus, contact hardness, plastic deformation resistance, and tissue mineral densities of cortical and trabecular bone regions of 55 iliac bone biopsies--12 SSBT patients (SSBT; aged 49-77), 11 age-matched untreated osteoporotic patients with vertebral fracture (Osteoporotic), 12 age-matched subjects without bone fracture (Age-Matched Normal), and 20 younger subjects without bone fracture (Young Normal)--were measured using nanoindentation and quantitative backscattered electron microscopy. For cortical bone nanoindentation properties, only plastic deformation resistance was different among the groups (p<0.05), with greater resistance to plastic deformation in the SSBT group compared to all other groups. For trabecular bone, all nanoindentation properties and mineral density of the trabecular bone were different among the groups (p<0.05). The SSBT group had greater plastic deformation resistance and harder trabecular bone compared to the other three groups, stiffer bone compared to the Osteoporotic and Young Normal groups, and a trend of higher mineral density compared to the Age-Matched Normal and Osteoporotic groups. Lower heterogeneity of modulus and contact hardness for cortical bone of the SSBT and trabecular bone of the Osteoporotic fracture groups, respectively, compared to the non-fractured groups, may contribute to fracture susceptibility due to lowered ability to prevent crack propagation. We tentatively conclude that, in addition to extremely low bone formation rate, atypical fractures in SSBT and/or long-term bisphosphonate treatment may be associated with greater mean plastic deformation resistance properties and less heterogeneous elastic properties of the bone.

Relating micromechanical properties and mineral densities in severely suppressed bone turnover patients, osteoporotic patients, and normal subjects

Mineralization of bone, from the tissue level to whole bones, is associated with mechanical properties. The relationship between bone tissue mineralization and micromechanical properties may be affected by age, disease, and drug treatment. Patients with severely suppressed bone turnover (SSBT) suffered atypical fractures while on bisphosphonate treatment. The role of tissue level mineralization in predicting material level properties of SSBT bone may be different from that of other osteoporotic patients and of normal subjects. The aim of this study was to compare the relationships between mineralization and micromechanical properties of bone biopsies from patients with SSBT, bisphosphonate-naive osteoporotic patients with typical vertebral fracture, and normal young and age-matched subjects. We used nanoindentation and quantitative backscattered electron microscopy to characterize the elastic modulus, contact hardness, plastic deformation resistance, and tissue mineralization of the biopsies at site-matched locations within each biopsy. The linear mineralization-mechanical property relationships were different among the groups with respect to the intercepts for only cortical bone tissue but not the slopes for cortical and trabecular bone tissues. For a given mineral density, there was a trend of greater plastic deformation resistance in SSBT cortical bone compared to young normal bone. Similarly, there was a trend of greater plastic deformation resistance in osteoporotic trabecular bone compared to young normal bone for a given mineral density. The age-matched normal group had higher elastic modulus and a trend of higher contact hardness compared to the young normal group for a given mineral density. However, the mechanical property-mineralization relationships within an individual were weak, and only 21 of 53 biopsies that were analyzed had at least one significant association between mineralization and a mechanical property measurement for either cortical or trabecular bone tissues. The average properties of microstructural regions (deep and superficial remodeling packets in trabecular bone; osteonal and interstitial regions in cortical bone) were consistent with mineral accumulation with tissue age, with the exception of the SSBT group. SSBT trabecular bone deep packets had higher hardness and plastic deformation resistance than superficial packets, but mineralization levels and tissue modulus were not different between packet types. We conclude that relationships between mineral and mechanical properties were different between fracture and normal groups and between young and old normal groups, and that atypical fracture may be associated with changed microstructural material properties and tissue level mineralization compared to osteoporotic patients with vertebral fracture and normal subjects. We hypothesize that tissue level bone quality may be an important determinant in fracture risk, such that tissue mineral density may predict different material properties in different patient groups.

Intestinal hyperabsorption of calcium and low bone turnover in hypercalciuric postmenopausal osteoporosis

Hypercalciuria of intestinal origin has been linked with bone loss in calcium nephrolithiasis and idiopathic osteoporosis. This retrospective data analysis was performed to explore potential pathogenetic link between intestinal hyperabsorption of calcium and postmenopausal osteoporosis. Data were retrieved from postmenopausal women who were evaluated for osteoporosis or osteopenia at the Mineral Metabolism Clinic of UT Southwestern Medical Center. A total of 319 patients underwent the test of calciuric response to oral calcium load to obtain an indirect measure of intestinal calcium absorption. Serum and urinary biochemistry and L2–L4 bone mineral density (BMD) were compared between five quintiles of calciuric response. There was a statistically significant trend toward a rise in 24-h urinary calcium and a decrease in urinary deoxypyridinoline (DPD) and BMD, with increasing order of quintiles. The presentation of those in the 1st quintile was consistent with vitamin D insufficiency or deficiency, with impaired calcium absorption, secondary hyperparathyroidism, and stimulated bone turnover (high normal urinary DPD). In contrast, patients in the 5th quintile displayed a picture of absorptive hypercalciuria of stone disease, with intestinal hyperabsorption of calcium, high or high normal urinary calcium and suppressed bone turnover (low or low normal urinary DPD). Thus, the assessment of intestinal calcium absorption in a seemingly homogeneous group of postmenopausal women with osteoporosis or osteopenia revealed a spectrum of calciuric response whose extremes may represent two physiologically distinct subtypes that have important diagnostic and therapeutic implications.

Medical Evaluation of Stone Disease

Medical management entails identification of causes of stone formation based largely on detection of abnormal urinary biochemistry (risk factors) (1), and application of dietary modification and pharmacological treatment designed to correct underlying disturbances (2). The importance of medical management is based on two important findings. Urolithiasis is characterized by a high recurrence rate (3–6). It is estimated that approx 60–80% of patients will form another stone within 10 yr of the first episode. Removal of existing stone does not prevent further stone formation (7).

Osteoporosis: How Should It Be Treated?

Osteoporosis develops as a result of imbalance between bone resorption and bone formation. A number of effective and safe therapies for osteoporosis are currently available, most of which are inhibitors of bone resorption. However, because osteoporosis is a complex and heterogeneous disease with different pathogenetic factors, defining the role of the different factors in its development is important in formulating a more selective approach to therapy. This review discusses the advantages and disadvantages of the currently available agents used in the management of osteoporosis.Osteoporosis develops as a result of imbalance between bone resorption and bone formation. A number of effective and safe therapies for osteoporosis are currently available, most of which are inhibitors of bone resorption. However, because osteoporosis is a complex and heterogeneous disease with different pathogenetic factors, defining the role of the different factors in its development is important in formulating a more selective approach to therapy. This review discusses the advantages and disadvantages of the currently available agents used in the management of osteoporosis.