Laurent Maïmoun

Bone loss in spinal cord-injured patients: from physiopathology to therapy.

Study design:Review article on bone metabolism and therapeutic approach on bone loss in patients with spinal cord injury (SCI).Objective:The first part aims to describe the process of bone demineralization and its effects on bone mass in patients with SCI. The second part describes and discusses the therapeutic approaches to limiting the alteration in bone metabolism related to neurological lesions.Setting:Propara Rehabilitation Center, Montpellier, France.Results:During the first 24 months postinjury, demineralization occurs exclusively in the sublesional areas and predominantly in weight-bearing skeletal sites such as the distal femur and proximal tibia, both of which are trabecular-rich sites. Reduced bone mass, in association with a modified bone matrix property and composition, is very likely at the origin of pathological fractures after minor trauma to which these patients are frequently exposed. Since these fractures may be asymptomatic yet may lead to complications, preventing and managing ‘neurological osteoporosis’ remains a considerable challenge. Two main approaches are considered: the first consists in applying a mechanical stimulus to the bone tissue by standing, orthotically aided walking or functional electrical stimulation (FES). The second uses medications, particularly antiresorptive drugs such as calcitonin or diphosphonates.Conclusion:To develop well-adapted treatments, a more precise understanding of bone loss etiology is needed. The current rehabilitation programs are based on the idea that the bone physiological changes observed in patients with SCI are due to immobility, but results indicate that alterations inherent to neurological damage may play an even greater role in inducing osteoporosis.

Strontium ranelate improves implant osseointegration

INTRODUCTION Endosseous implantation is a frequent procedure in orthopaedics and dentistry, particularly in the aging population. The incidence of implant failure, however, is high in situations where the bone at the site of implantation is not of optimal quality and quantity. Alterations of bone turnover and changes in intrinsic bone tissue quality have potentially negative effects on optimal osseointegration. Strontium ranelate, which acts on both resorption and formation, and improves biomaterial properties, is hypothesized to improve osseointegration and this hypothesis was tested here. MATERIALS AND METHODS Titanium implants were inserted into the proximal tibias of thirty 6-month-old Sprague-Dawley female rats. During the 8 weeks following implantation, animals received orally strontium ranelate (SrRan) 5 days a week (625 mg/kg/day) or saline vehicle. Pull-out strength, microCT and nanoindentation were assessed on the implanted tibias. RESULTS SrRan significantly increased pull-out strength compared to controls (+34%). This was associated with a significant improvement of bone microarchitecture around the implant (BV/TV+36%; Tb.Th+13%; Conn.D+23%) with a more plate-shape structure and an increase in bone-to-implant contact (+19%). Finally, strontium ranelate had a significant beneficial effect on parameters of bone biomaterial properties at both cortical (modulus+11.6%; hardness+13%) and trabecular areas (modulus+7%; hardness+16.5%). CONCLUSIONS SrRan is an antiosteoporotic agent that increased mechanical fixation of the implant. The improvement of pull-out strength was associated with an improvement of implant osseointegration with both a positive effect on bone microarchitecture and on bone biomaterial properties in the vicinity of the implant. These current results may support potential benefits of strontium ranelate in orthopaedic and dental surgery to enhance osseointegration.

Phenotypical, Biological, and Molecular Heterogeneity of 5α-Reductase Deficiency: An Extensive International Experience of 55 Patients

CONTEXT In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential. OBJECTIVE The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis. SETTING The study was performed at Montpellier University Hospital. PATIENTS We studied a cohort of 55 patients with srd5A2 gene mutations. MAIN OUTCOME MEASURE(S) Genetic analysis of srd5A2 was conducted. RESULTS Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively. CONCLUSIONS In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.

Effects of physical activity on bone remodeling

Physical exercise is recommended to improve bone mass in growing children and decrease bone loss in elderly men and women. However, the specific mechanisms by which exercise influences bone metabolism are still not thoroughly understood. The effect of physical activity on the skeleton is generally evaluated by dual-energy x-ray absorptiometry, which measures bone mineral density. However, a relatively long period is needed to detect even a minor variation in bone mineral density with this technique, limiting its usefulness. Bone biochemical markers that reflect the cellular activities of bone formation and resorption are thus also useful tools, both to monitor the acute effects of exercise on bone remodeling and to investigate the mechanisms of exercise-induced changes in bone mass. This article describes the effects of physical activity on bone remodeling in various types of population. The comparison of sedentary individuals and athletes with many years of high-volume sports practice, for example, has clarified some of the long-term effects of exercise. Moreover, the acute variation in bone cell activities after brief exercise or a training program is here examined. The interpretation of results is difficult, however, because of the many parameters, such as age, that are involved. The various populations are therefore categorized to reflect the biological factors implicated in the modulation of bone marker response during exercise.

Changes in Osteoprotegerin/RANKL System, Bone Mineral Density, and Bone Biochemicals Markers in Patients with Recent Spinal Cord Injury

This study analyzed the temporal and regional variations in bone loss and explored bone cell activities via biochemical markers during an extended follow-up in patients with spinal cord injury (SCI). In parallel, the possible role of the osteoprotegerin (OPG)/RANKL system in disuse osteoporosis was investigated. Seven male patients with acute and complete SCI (31.3 ± 9.5 years) and 12 able-bodied (AB) men (26.9 ± 4.2 years) participated in the study. Measurements were performed 16, 24, 36, 48, and 71 weeks after injury. At week 16, marked calcium homeostasis disturbance and a concomitant increase in bone resorption markers were observed, reflecting an intense bone degradation process. Resorption activity decreased continuously with time. Contrasting with the great rise in the resorption markers, the bone formation markers showed little variation. During the period of investigation, a loss in bone mineral density (BMD) was demonstrated for the total body (−4.3%), pelvis (−15.7%) and lower limbs (−15.2%), whereas BMD did not change at the lumbar spine, upper limbs, or skull. At all stages, SCI patients had lower serum RANKL levels and higher serum OPG levels than did AB controls, but no significant variation with time was observed for either cytokine. These findings suggest that bone resorption persisted long after SCI and specifically affected BMD at sublesional sites. The marked modification of serum OPG/RANKL levels in SCI patients suggests that this system is affected, in disuse osteoporosis. However, the precise biologic role of the OPG/RANKL system in the bone tissue of SCI patients has yet to be determined.

Testosterone Is Significantly Reduced in Endurance Athletes without Impact on Bone Mineral Density

Aims: To compare the basal plasma reproductive hormonal profile in three groups of athletes involved in different training programs, and to define the relationship between androgen level and bone mineral density (BMD) in male athletes. Methods: Basal serum total testosterone (TT), free androgen index (FAI), sex hormone-binding globulin (SHBG), cortisol, cortisol to TT ratio, luteinizing hormone (LH), estrogen and BMD were evaluated in cyclists (CY; n = 11), triathletes (TR; n = 14) and swimmers (SW; n = 13) and compared with less active controls (n = 10). Results: TT and FAI levels were lower (p < 0.05) in CY and TR, whereas the ratio of cortisol to TT was increased in CY only (p < 0.05). No alteration in serum LH, SHBG, estrogen or cortisol concentration was observed. BMD was higher in the proximal femur in TR (p < 0.05). No BMD or hormonal differences were found in SW. Conclusion: Only the endurance training of CY and TR induced androgen deficiency without apparent alteration of BMD.

Effects of physical activities that induce moderate external loading on bone metabolism in male athletes

Sports characterized by little or moderate weight bearing or impact have a low osteogenic effect. However, the action of such sports on bone turnover remains unclear. The objective of this study was to determine the effect on bone remodelling of physical activities that induce moderate external loading on the skeleton. Thirty-eight male athletes aged 18–39 years (cyclists, n = 11; swimmers, n = 13; triathletes, n = 14) and 10 age-matched sedentary controls aged 22–35 years participated in the study. The study combined measurement of bone mineral density by dual-energy X-ray absorptiometry and bone turnover assessment from specific biochemical markers: serum bone-specific alkaline phosphatase, osteocalcin, urinary type I collagen C-telopeptide and calcium. Compared with the controls and swimmers, adjusted bone mineral density was higher (P < 0.05) in triathletes at the total proximal femur and lower limbs. No differences in bone mineral density were found between cyclists, swimmers and controls. Compared with controls, osteocalcin was higher (P < 0.05) in triathletes and swimmers and urinary type I collagen C-telopeptide was higher in swimmers only. Serum bone-specific alkaline phosphatase was lower (P < 0.05) in cyclists than in all other groups. In conclusion, an osteogenic effect was found only in triathletes, mainly at bone sites under high mechanical stress. Bone turnover differed in athletes compared with controls, suggesting that bone turnover may be sport-practice dependent. Despite some encouraging observations, it was not possible to show that changes in the bone remodelling process were sport-discipline dependent.

Effect of Physical Activity on Calcium Homeostasis and Calciotropic Hormones: A Review

Physical exercise has frequently been shown to improve bone mass, especially at load-bearing bone sites. It is widely acknowledged that the anabolic effects of exercise on bone tissue are related to the application of mechanical constraints, but part of the osteogenic response may be due to other factors. In particular, various hormonal parameters that are modified by training, such as insulin-like growth factor-1 and sexual hormones, may modulate the bone response. In contrast, little is known about the involvement of calciotropic hormones in the adaptation mechanism of bone tissue. These hormones, which include parathyroid hormone, vitamin D metabolites, and calcitonin, are highly implicated in the regulation of both bone remodeling and calcium homeostasis. In addition to their direct action on bone cell activity, these hormones act on various target tissues such as kidney and intestine. This article describes the acute and long-term effects of exercise on both calcium homeostasis and calciotropic hormones in various populations. It clearly shows that exercise modifies calcium homeostasis and calciotropic hormone levels and that the variations in response are modulated by parameters related to exercise, including duration and intensity, as well as by individual characteristics such as age, sex, and training status.

Response of bone metabolism related hormones to a single session of strenuous exercise in active elderly subjects

Objective: To evaluate the effect of strenuous exercise on bone metabolism and related hormones in elderly subjects. Methods: Twenty one active elderly subjects (11 men and 10 women; mean age 73.3 years) showing a mean theoretical Vo2max of 151.4% participated. Concentrations of plasma ionised calcium (iCa), serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D), and 1.25-dihydroxy-vitamin D3 (1.25(OH)2D3), as well as the bone biochemical markers type I collagen C-telopeptide for bone resorption and osteocalcin and bone alkaline phosphatase for bone formation, were analysed before and after a maximal incremental exercise test. Results: At basal level, iPTH was positively correlated with age (r = 0.56, p<0.01) and negatively correlated with 25(OH)D (r = −0.50; p<0.01) and 1.25(OH)2D3 (r = −0.47; p<0.05). Moreover, 25(OH)D and 1.25(OH)2D3 levels were negatively correlated with age (r = −0.50, p<0.01 and r = −0.53, p<0.01, respectively). After exercise, iCa and 25(OH)D decreased (p<0.001 and p = 0.01, respectively) while iPTH increased (p<0.001). The levels of 1.25(OH)2D3, bone biochemical markers, haematocrit, and haemoglobin were unchanged. The variations in iCa and 25(OH)D were not related to age and/or sex. The iPTH variation was directly related to basal iPTH levels (p<0.01) and indirectly related to age. Conclusions: In active elderly subjects, strenuous exercise disturbed calcium homeostasis and bone related hormones without immediate measurable effect on bone turnover. Although an increase in iPTH could have an anabolic action on bone tissue, our findings from our short term study did not allow us to conclude that such action occurred.

Osteoporosis in Persons With Spinal Cord Injury: The Need for a Targeted Therapeutic Education

OBJECTIVES To identify circumstances surrounding the onset of fracture and common risk factors in persons with spinal cord injury (SCI) and to suggest an alternative or complement to the pharmacologic approach by evaluating the need for a prospective study based on the impact of a targeted therapeutic education on risk management of fractures in this population. DESIGN Retrospective study. SETTING Hospital and Rehabilitation Center Setting. PARTICIPANTS Women (n=7) and men (n=25; N=32; with ≥1 fracture after the initial SCI that occurred at home or in a hospital setting; mean ± SD age, 53±12y at the time of clinical review) with bone mineral density (BMD) measurements. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Demographics, main circumstances of onset, and complications of fractures, as well as transversal bone mineral density evaluation. RESULTS Nine patients had more than 1 fracture and 23 patients had only 1 fracture (total, 43 fractures; mean age at onset of fracture, 49±12y; median time since injury, 13.9y; mean delay in diagnosis, 6.5±15d). Fractures occurred mostly in the lower limbs. The circumstances of onset of these fractures were different and very stereotyped. In 3 cases, no trauma was reported. The most frequent mechanisms identified were forced maneuvers by the patient or a third party and falls. In 10 cases, the fracture occurred during a wheelchair transfer with forced maneuver or a fall from the wheelchair. Twenty-five patients were confined to bed after the fracture (mean duration of bed confinement, 18±28d; range, 0-120d). Postfracture follow-up showed that for 43 cases of fractures, 19 had at least 1 orthopedic complication, 15 had local complications, and 23 had general complications. Patients (23 of 32) benefited from dual-energy X-ray absorptiometry to assess BMD a few months or years after the fracture (mean femoral neck BMD, 0.574±0.197g/cm²; mean femoral neck T score, -3.8±1.5). CONCLUSION With this retrospective analysis of common risk factors and circumstances of onset of secondary fractures, there is a clear future for a prospective study to evaluate the impact of targeted therapeutic education on risk factors for secondary fractures in patients with SCI.