Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Cost-effective osteoporosis treatment thresholds in Greece.

UNLABELLED: A Greek-specific cost-effectiveness analysis determined the FRAX-based intervention thresholds. Assuming a willingness to pay of 30,000 , osteoporosis treatment is cost-effective in subjects under the age of 75 with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, respectively, while for older patients, the same thresholds are raised to 5 and 15 %. INTRODUCTION: The purpose of this study was to determine the FRAX calculated fracture probabilities at which therapeutic intervention can be considered as cost-effective in the Greek setting. METHODS: A Markov cohort model was populated with Greek data, and quality-adjusted life years (QALYs) were used to calculate the cost-effective thresholds for an annual medication cost of 733.7 by gender and age. Average FRAX-based 10-year probabilities for both major osteoporotic and hip fractures were multiplied by the model-derived relative risk at which a cost of 30,000 for each QALY gained was observed for treatment versus to no intervention. RESULTS: A biphasic intervention threshold model is supported by our findings. Osteoporosis treatment becomes cost-effective when absolute 10-year probabilities for hip and major osteoporotic fractures reach 2.5 and 10 %, respectively, among both men and women under the age of 75. For older subjects, the proposed intervention thresholds are raised to 5 and 15 % 10-year probability for hip and major osteoporotic fractures, respectively. CONCLUSIONS: Cost-effective osteoporosis treatment may be facilitated in Greece if FRAX algorithm is used to identify subjects with 10-year probabilities for hip and major osteoporotic fractures of 2.5 and 10 %, under the age of 75, while for older patients, the relevant thresholds are 5 and 15 %, respectively.

Analgesic effect of nasal salmon calcitonin during the early post-fracture period of the distal radius fracture.

OBJECTIVES: To investigate the analgesic effect of nasal salmon calcitonin on the post-fracture period of distal radius fracture. METHODS: In this prospective randomized double-blind study, forty-one postmenopausal women with a recent distal radius fracture treated conservatively were randomly assigned to receive either 200 IU of intranasal salmon calcitonin or placebo daily for 3 months following fracture. The assessment of the patient's pain was recorded using the Visual Analogue Scale (VAS). RESULTS: The average age of the calcitonin group was 67.11 (SD, ±8.68) years and 64.91 (SD, ±7.48) of the placebo group. In the calcitonin group, the mean VAS score improved from 4.05 to 0.53 while in the placebo group from 3.36 to 0.32. A higher decrease of VAS score during the first post-fracture period was observed in the calcitonin group. CONCLUSIONS: In the study, there is a statistically significant calcitonin mediated analgesic effect in the immediate post fracture period (at 10 days) when compared to placebo group. These results are in accordance with literature referring to the analgesic effect of calcitonin in the acute osteoporotic vertebral compression fracture. Thus calcitonin administration could be recommended to a short term course in acute osteoporotic conservatively treated distal radius fractures.

Management of bisphosphonate-related osteonecrosis of the jaw: a literature review.

Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non-bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high-dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate-related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen.

Incidence of hip fractures in Greece during a 30-year period: 1977-2007.

UNLABELLED: The incidence of hip fractures doubled in Greece from 1977 to 2007 among people aged 50 and over. A mild decrease was observed after 2002, although the future trend cannot be safely anticipated at the moment. Half of all hip fractures in 2007 were derived from the age group of 80 and over. INTRODUCTION: The purpose of this study was to determine the incidence of hip fractures during a 30-year period in Greece among people aged 50 and over and to document possible alterations in secular trends. METHODS: We studied hip fractures during 2007 and compared them with those of previous years starting from 1977 with an in-between 5-year interval (1977, 1982, 1987, 1992, 1997, 2002). Age- and sex-specific incidence was calculated, and secular trends were recorded. The relative risk of hip fracture in every age group was estimated according to the corresponding incidence of 1977. RESULTS: The adjusted incidence of hip fractures increased approximately 100 % throughout the study; it progressively increased from 1977 to 2002 and exhibited a mild significant decrease thereafter. The relative risk of hip fractures among subjects aged 60-69 in 2007 has declined compared with 1977 [0.85, 95 % confidence intervals (CI) 0.79-0.92, p < 0.0005]. Among people aged 70-79, an increased relative fracture risk (1.53, 95 % CI 1.45-1.61, p < 0.0005) was estimated in 2007 compared with 1977. People ≥80 years old were responsible for half of the hip fractures in 2007 but only for the 22.5 % of fractures in 1977. The relative fracture risk in people aged ≥80 was 2.81 times higher (95 % CI 2.64-2.98, p < 0.0005) in 2007 than in 1977. CONCLUSIONS: The incidence of hip fractures doubled during the last 30 years among people aged ≥50 years, although a mild decrease was observed in almost all age groups after 2002. The most affected group is 80 and over.

Balloon kyphoplasty and vertebroplasty in the management of vertebral compression fractures.

Vertebral compression fractures (VCFs) are the most prevalent fractures in osteoporotic patients. The classical conservative management of these fractures is through rest, pain medication, bracing and muscle relaxants. The aim of this paper is to review prospective controlled studies comparing the efficacy and safety of minimally invasive techniques for vertebral augmentation, vertebroplasty (VP) and balloon kyphoplasty (BKP), versus non-surgical management (NSM). The Fracture Working Group of the International Osteoporosis Foundation conducted a literature search and developed a review paper on VP and BKP. The results presented for the direct management of osteoporotic VCFs focused on clinical outcomes of these three different procedures, including reduction in pain, improvement of function and mobility, vertebral height restoration and decrease in spinal curvature (kyphosis). Overall, VP and BKP are generally safe procedures that provide quicker pain relief, mobility recovery and in some cases vertebral height restoration than conventional conservative medical treatment, at least in the short term. However, the long-term benefits and safety in terms of risk of subsequent vertebral fractures have not been clearly demonstrated and further prospective randomized studies are needed with standards for reporting. Referral physicians should be aware of VP/BKP and their potential to reduce the health impairment of patients with VCFs. However, VP and BKP are not substitutes for appropriate evaluation and treatment of osteoporosis to reduce the risk of future fractures.

Decreased tibial bone strength in postmenopausal women with aseptic loosening of cemented femoral implants measured by peripheral quantitative computed tomography (pQCT).

Aseptic loosening after total hip arthroplasty is related to bone loss of the operated leg. The aim of the present study was to investigate the effect of aseptic loosening on volumetric bone mineral density (vBMD) and bone geometry in the operated leg, in postmenopausal women with a loosened cemented femoral implant using peripheral quantitative computed tomography (pQCT). We matched 12 postmenopausal women with aseptic loosening of cemented femoral implant, with 12 women without aseptic loosening (control group) according to age, BMI, and years from operation. All patients underwent pQCT of both tibias, DXA of the lumbar spine, and determination of biochemical markers of bone turnover. pQCT values in the control group as well as the nonoperated legs between groups had no significant difference. In the aseptic loosening group, there was significant reduction of cortical vBMD (cort vBMD) at 14% and 38% sites (cortical site), cortical thickness at 38% site, and of polar stress strength index (SSIp) at 14% site (transition zone) in the operated compared with the nonoperated leg. Similarly, there was significant reduction of cort vBMD at 14% and 38% sites and total vBMD and trabecular vBMD (trab vBMD) at the 14% site in the operated legs between the two groups. The aseptic loosening group had increased osteocalcin and serum collagen cross-linked N- and C-telopeptides (sNTX and sCTX) levels compared with controls. Aseptic loosening is associated with significant decrease of cortical and trabecular vBMD, and impairment of bone geometry and strength only in the operated leg. Increased bone turnover probably represents a local phenomenon, and is not associated with systemic skeletal disease.

Calcitonin effect on Achilles tendon healing. An experimental study on rabbits.

OBJECTIVE: A positive potential effect of Calcitonin (CT) on Achilles tendon healing was investigated as well as the ability of MRI to follow the tendon healing process. MATERIALS AND METHODS: A standardized tenotomy of the Achilles tendon was performed on forty-two rabbits. Twenty-one animals received daily 21 IU /kg Calcitonin intramuscularly (treatment group CT) during the experiment and the remaining received saline solution (control group P). Seven animals from each group were killed at one, two and three weeks postoperatively. All animals had serial MRI scans and tendon samples underwent biomechanical and histological testing. RESULTS: For both groups, animals of the same subgroup showed statistically significant difference in signal intensity values of MRI between the 1st and 3rd week (p<0.001) and between the 2nd and 3rd week (p<0.001). Signal intensity values of MRI didn't show any differences between animals under treatment and controls measured at 1st (p=0.23), 2nd (p=0.23) and 3rd (p=0.53) postoperative week. Tendon samples from group CT showed statistically significant difference in ultimate tensile strength compared to controls at 2 (p<0,0005) and 3 (p<0,0005) weeks post-surgery. Histology showed a positive Calcitonin effect at all tendon healing stages. CONCLUSION: It is suggested that Calcitonin enhances Achilles tendon healing process.

Changes in biochemical indices of bone metabolism in post-menopausal women following a dietary intervention with fortified dairy products.

BACKGROUND: In southern Europe, calcium supplementation alone is a common practice for osteoporosis prevention. The present study aimed to examine whether calcium supplementation alone could be as effective in achieving favourable changes on bone metabolism indices of Greek post-menopausal women as a holistic dietary approach combining consumption of dairy products fortified with calcium and vitamin D(3) and nutrition counselling sessions for five winter months. METHODS: A sample of 101 post-menopausal women was randomised to a dairy intervention group (IG: n = 39), receiving approximately 1200 mg of calcium and 7.5 microg of vitamin D(3) per day via fortified dairy products and attending biweekly nutrition counselling sessions; a calcium-supplemented group (SG: n = 26) receiving a total of 1200 mg calcium per day; and a control group (CG: n = 36). RESULTS: Regarding insulin-like growth factor (IGF)-I, a higher increase was observed for the IG compared to the changes in the CG and the SG (P = 0.049). Regarding serum parathyroid hormone (PTH) levels, the increase observed in the CG was higher than the changes observed in the other two groups but the differences were of marginal significance (P = 0.055). No significant differences were observed among groups regarding the changes in serum osteocalcin and type I collagen cross-linked C-telopeptide levels. CONCLUSIONS: The application of a holistic intervention approach combining nutrition counselling and consumption of fortified dairy products for five winter months induced some more favourable changes in IGF-I and PTH levels compared to calcium supplementation alone. Intervention periods longer than 5 months might be required to achieve significant differences among groups for bone remodelling biomarkers as well.

Rehabilitation after falls and fractures.

Falls are one of the most common geriatric problems threatening the independence of older persons. Elderly patients tend to fall more often and have a greater tendency to fracture their bones. Fractures occur particularly in osteoporotic people due to increased bone fragility, resulting in considerable reduction of quality of life, morbidity, and mortality. This article provides information for the rehabilitation of osteoporotic fractures pertaining to the rehabilitation of the fractured patient, based on personal experience and literature. It also outlines a suggested effective and efficient clinical strategy approach for preventing falls in individual patients.

Lack of association between vitamin D and calcitonin receptor gene polymorphisms and forearm bone values of young Greek males.

UNLABELLED: INTRODUCTION--HYPOTHESIS: Since the genetic bases of bone mass regulation in males are still poorly understood and the role of calciotropic hormones on bone mineral metabolism is absolute, our hypothesis is based on the certainty that specific genetic polymorphism will contribute, at least, on bone mass values. Our objective was to examine the relative contribution of genetic variables to the regulation of bone values in a population of young healthy men, focusing on the BsmI polymorphism of vitamin D receptor (VDR) gene and the AluI polymorphism of calcitonin receptor (CTR) gene. METHODS: Areal bone mineral density (aBMD), bone mineral content (BMC) and geometrical areas at specific skeletal sites of the forearm, of 301 healthy Caucasian young men, aged 18-25, were assessed by single X-ray absorptiometry (Osteometer DTX-100). VDR and CTR alleles were determined by BsmI and AluI endonuclease restriction fragment analyses. Analysis of covariance was used as a statistical model. RESULTS: No significant differences in the forearm aBMD, BMC or in area values were observed between the VDR and CTR genotypes. Findings did not change after adjusting for demographic characteristics. CONCLUSIONS: The BsmI and AluI polymorphisms are not related to the forearm bone values either reflecting mass or geometrical variables in this male population.

Cortical bone response adjacent to applied light orthodontic forces in ovariectomized rats.

Cortical bone response to experimental orthodontic forces has not been adequately described in the available literature. The aim of this study was to investigate the application of light orthodontic forces on the cortical bone adjacent to the point of their application, in normal and ovariectomized rats. At the age of eight months, twenty-four female rats were divided equally into two groups: normal (group A) and ovariectomized (group B). A 20 gr* orthodontic force was applied to the maxillary right first molars in all animals for 14 days. Histological examination of the maxillary cortical bone, at the level of the first molar of the upper jaw, was performed on both sides of all animals. It was found that light orthodontic forces applied to the upper right first molars of normal rats result in thinner cortical bone with increased osteoblastic activity, normal lamellar orientation and normal distribution of osteocytes compared to the non-affected contralateral side. In ovariectomized rats it was found that light orthodontic forces applied to the upper right first molars result in thickening of the cortex, in comparison to the respective area of the opposite side where no orthodontic forces were applied. It seems that experimental light orthodontic forces, in rats, affect cortical bone remodeling differently, according to their hormonal status, in areas adjacent to the applied forces.

Bone loss and mechanical properties of tibia in spinal cord injured men.

AIM: The effects of Spinal Cord Injury (SCI) on bone in paralyzed areas are well documented but there are few data for the importance of the level of injury in the decrease of mechanical strength in paralyzed legs. The aim of the present study was to describe bone loss of the separate compartments of trabecular and cortical bone in spinal cord injured men and to compare possible changes in mechanical properties of tibia with the neurological level of injury. MATERIALS AND METHODS: Fifty men were included in this study: 39 had complete SCI in chronic stage. As chronic stage, we considered paraplegia >1.5 years (yrs). Men were separated as follows: Group A (18 men, high paraplegia: Thoracic (T)4-T7 level, mean age: 33 yrs, duration of paralysis: 5.9 yrs) and group B (21 men, low paraplegia: T8-T12 level, mean age: 39 yrs, duration of paralysis: 5.6 yrs) in comparison with 11 healthy men as a control group (C) of similar age, height, and weight. None of the subjects was given bone acting drugs. The neurological profile of each patient was assessed according to the American Spinal Injury Association (ASIA). All subjects were measured by peripheral quantitative computed tomography (pQCT). Measurements were performed at the tibia with a Stratec XCT 3000 (Stratec Medizintechnik, Pforzheim, Germany) scanner. The distal end of the tibia was used as an anatomical marker. The bone parameters, bone mass density (BMD) trabecular, BMD total, BMD cortical, and cortical thickness have been measured at 4% and 38%, respectively, of the tibia length proximal to this point, and the periosteal and endocortical was measured at 14% of the tibia. We calculated stress strain index (SSI), a bone strength estimator derived from the section modulus, and the volumetric density of the cortical area at 14% (SSIPol2) and 38% (SSIPol3) of the tibia length proximal to the distal end of the tibia. RESULTS: In both groups A and B most bone mass parameters were statistically decreased in comparison with controls. In each group we calculated the median deltaSSI(3-2) (SSIPol3 - SSIPol2). In the paraplegic groups Spearman correlation coefficient between duration of paralysis and deltaSSI(3-2) was in group A: r=-0.178, p=N.S. and group B: r=0.534, p=0.027, respectively. CONCLUSION: Despite the similar paralytic effect on bone in all paraplegic patients in our study and because of the non-significant duration of paralysis between paraplegic groups (p=0.87), the two paraplegic groups act differently in mechanical properties of the tibia. In addition, group A patients in respect to the level of injury, are susceptible to autonomic dysreflexia as a result of the disruption of the autonomic nervous system pathways. These results suggest that neurogenic factors are influencing geometric bone parameters.

Strontium ranelate: a novel treatment in postmenopausal osteoporosis.

Strontium ranelate (SR) is a novel antiosteoporotic agent, electively concentrated in positions of active bone formation, and especially onto the crystal surface that allows permanent exchanges with extracellular fluid. Although the mechanism(s) of action is still under rigorous research, SR appears to reduce bone resorption by decreasing osteoclast differentiation and activity and to stimulate bone formation by increasing replication of preosteoblast cells, leading to increased matrix synthesis. In the placebo-controlled, phase III trial spinal osteoporosis therapeutic intervention (SOTI) (no=1442; mean age 69 years), there was a 41% decrease over 3 years in the number of patients with new vertebral fractures in the SR (2 g/day) group versus placebo (P<0.001), already detected after 12 months (49% lower risk, P<0.001). The phase III treatment of peripheral osteoporosis (TROPOS) study assessed the efficacy of SR (2 g/day) in preventing nonvertebral fractures in postmenopausal osteoporosis (no=4932; mean age 77 years). SR reduced nonvertebral fracture risk by 16% versus placebo (P=0.04) and hip fracture risk by 36% (P=0.031) in osteoporotic patients older than 74 years. Thus SR is an effective and safe treatment for vertebral and hip osteoporosis with a unique mode of action.

Protective effect of plant extract from Onobrychis ebenoides on ovariectomy-induced bone loss in rats.

OBJECTIVE: Certain plant extracts have been the object of recent studies due to their mild estrogenic action and their possible potential role in osteoporosis prevention and/or treatment. The present study was undertaken to investigate the possible protective effect of the aqueous solution of the plant Onobrychis ebenoides, with proven in vitro mild estrogenic action, on bone mass loss of the ovariectomized (Ovx) rat experimental model of osteoporosis. METHODS: Forty intact female mature (10-month-old) Wistar rats were separated into three groups: Ovx, Ovx plus plant extract (Ph) and sham-operated (control). Ph administration in the drinking water at a dose of 300 mg/kg body weight/day commenced immediately after Ovx. Bone mineral density (BMD) values, percentage change from the baseline measurement and histomorphometry of the tibia, as well as body and uterine weight, were examined and compared between groups. RESULTS: Comparison of BMD absolute values of the whole tibia of Ovx + Ph and Ovx animals at both 3 and 6 months post-Ovx were highly significant (p < 0.0005), showing a protective effect on treated animals. The extract did not appear to have such a beneficial effect on BMD of the proximal tibia of the treated animals compared to the Ovx animals after 3 months; however, a significant protective effect was observed at 6 months post-Ovx in treated animals compared to the Ovx (p = 0.015). When the % changes from baseline measurement of the whole tibia of Ovx + Ph and controls were compared, there was no significant difference at 3 or 6 months, demonstrating a highly protective effect; the respective comparisons of proximal tibia % changes did not display such protection. Body and uterine weight comparisons showed no significant difference between Ovx and treated rats, whereas, the level of significance for each group compared to controls was p < 0.0005. CONCLUSIONS: The Ph studied showed a highly significant protective effect on BMD of the whole tibia of Ovx rats after 3 and 6 months of treatment, compared to the non-treated animals. Its effect on the proximal tibia was less pronounced, but also statistically significant compared to non-treated rats after 6 months. The lack of significant effect on body and uterine weight is in favor of its selective estrogen receptor modulator-like activity, and merits further studies.