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1.  Cutaneous Side Effects of Antiosteoporosis Treatments 
Cutaneous adverse reactions are reported for many therapeutic agents and, in general, are observed in between 0% and 8% of treated patients depending on the drug. Antiosteoporotic agents are considered to be safe in terms of cutaneous effects, however there have been a number of case reports of cutaneous adverse reactions which warrant consideration. This was the subject of a working group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, which focused on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. This position paper was drafted following these discussions and includes a flowchart for their recognition. Cutaneous adverse reactions observed with antiosteoporotic agents were reviewed and included information from case reports, regulatory documents and pharmacovigilance. These reactions ranged from benign effects including exanthematous or maculopapular eruption (drug rash), photosensitivity and urticaria, to the severe and potentially life-threatening reactions of angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome and toxic epidermal necrolysis. A review of the available evidence demonstrates that cutaneous adverse reactions occur with all commonly used antiosteoporotic treatments. Notably, there are reports of Stevens Johnson syndrome and toxic epidermal necrolysis for bisphosphonates, and of DRESS and toxic epidermal necrolysis for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases). In general, with proper management and early recognition, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration and systemic corticosteroids if necessary, the prognosis is positive.
doi:10.1177/1759720X10387202
PMCID: PMC3383534  PMID: 22870464
antiosteoporosis treatments; cutaneous adverse reactions; hypersensitivity reactions; osteoporosis
2.  Fracture prevention in postmenopausal women 
Clinical Evidence  2011;2011:1109.
Introduction
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcium, calcium plus vitamin D, clodronate, denosumab, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate.dfsg
Key Points
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years. About 13% of people die in the year after a hip fracture, and most survivors lose some or all of their previous independence.
Alendronate, risedronate, zoledronate, denosumab, and parathyroid hormone reduce vertebral and non-vertebral fractures compared with placebo. Etidronate, ibandronate, pamidronate, and raloxifene reduce vertebral fractures, but have not been shown to reduce non-vertebral fractures.Raloxifene protects against breast cancer, but increases venous thromboembolic events and stroke compared with placebo. Strontium ranelate reduces vertebral and, to some extent, non-vertebral fractures. Clodronate may reduce non-vertebral fractures at 3 years, but its effects on rate of vertebral fracture are unclear.
CAUTION: Hormone replacement therapy may reduce fractures, but it increases the risk of breast cancer and cardiovascular events. The risks of adverse effects of treatment are thought to outweigh the beneficial effects of hormone replacement therapy in prevention of fractures.
Combined calcium plus vitamin D or vitamin D analogues alone may reduce vertebral and non-vertebral fractures, but trials have given inconclusive results. Monotherapy with calcium or vitamin D has not been shown to reduce fractures, and calcium alone may potentially be associated with an increased risk of cardiovascular adverse effects.
We don't know whether multifactorial non-pharmacological interventions including environmental manipulation or regular exercise reduce the risk of fractures. Hip protectors may reduce the risk of hip fractures in nursing-home residents, but compliance tends to be low.
Calcitonin was included in an earlier version of this review. However, in light of a drug alert (http://www.ema.europa.eu/ema/) it was removed from this version because of new harms data. It will be covered in the next update of this review when these new harms data can be incorporated.
PMCID: PMC3217780  PMID: 21542947
3.  Results of Indirect and Mixed Treatment Comparison of Fracture Efficacy for Osteoporosis Treatments: a Meta-Analysis 
Purpose
This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, mixed treatment comparison [MTC]) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials.
Methods
Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacologic therapies versus placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab versus other agents.
Results
Using data from 33 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced non-vertebral and hip fracture while alendronate, strontium ranelate, and teriparatide significantly reduced risk for non-vertebral fractures. MTC showed denosumab as more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures.
Conclusions
The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacologic therapies for postmenopausal osteoporosis.
doi:10.1007/s00198-012-2068-9
PMCID: PMC3662000  PMID: 22832638
osteoporosis; treatment efficacy; postmenopausal women; meta-analysis; mixed treatment comparison
4.  Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications 
Osteoporosis International  2012;23(Suppl 1):S1-S23.
Summary
Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection.
Introduction
The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound.
Methods
The present document is the result of a national consensus, based on a systematic and critical review of the literature.
Results
Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed.
Conclusion
Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices.
doi:10.1007/s00198-011-1891-8
PMCID: PMC3273686  PMID: 22311111
Bisphosphonate; Calcium; Denosumab; Osteoporosis; SERM; Strontium ranelate; Vitamin D
5.  Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis 
Osteoporosis International  2009;20(10):1663-1673.
Summary
Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis.
Introduction
Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate.
Methods
A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated.
Results
Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction = 0.67, p < 0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p < 0.001). QoL, assessed by the QUALIOST®, was significantly better (p = 0.025), and patients without back pain were greater (p = 0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups.
Conclusion
In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.
doi:10.1007/s00198-008-0825-6
PMCID: PMC2744775  PMID: 19153678
Bone densitometry; Menopause; Osteoporotic fracture; Osteoporosis treatment; Strontium ranelate
6.  Strontium Ranelate: The Pathophysiological Rationale 
Skeletal metabolism and the replacement of damaged tissue with the same amount of intact bone depends on the correct balance between bone formation and bone resorption.
The existence of an imbalance between bone formation and resorption is a concept central to understanding of the pathophysiology of osteoporosis and the reduction of fracture risk.
With aging, the volume of bone that is formed during the bone remodelling process and after injury is less than the volume absorbed during the bone resorption phase; this results in bone loss and increased bone fragility. In addition to bone mineral density, many other properties of bone are determined by the balance between bone formation and bone resorption. A bone that is biomechanically more fragile is also a bone that consolidates more slowly after a fracture event. Although the fracture healing stages are the same even in the presence of osteoporosis, recent studies have shown a slowdown in the process of consolidation when osteoporosis is present. In particular, strategies to reduce fracture risk and facilitate the process of consolidation of the fracture may be a primary criterion for selection.
The ability to modulate anabolic and catabolic phenomena in the skeleton, both locally and systemically, opens up a new horizon for the reduction of fracture risk and the enhancement of bone healing, particularly when the bone is qualitatively and/or quantitatively compromised.
Clinical research has recently allowed the development of therapies, such as treatment with strontium ranelate, able to increase production of bone matrix by osteoblasts and to act positively on the distribution of the skeletal microarchitecture. Strontium ranelate is able to rebalance bone turnover in favour of the formation of more resistant and elastic bone, by stimulating osteoblasts and inhibiting the resorptive activity of osteoclasts, thereby ensuring rapid and lasting protection against the risk of fractures. In vitro studies have shown that the drug is able to promote replication of the first pre-osteoblasts and their differentiation into mature osteoblasts and osteocytes interacting with the receptor CaSR and through the increased synthesis of OPG. Thanks, again, to the participation of the CaSR receptor, but also by reducing the production of RANKL, strontium ranelate decreases the resorptive activity of osteoclasts. The anabolic action of strontium ranelate in terms of mineral apposition rate in both cortical and trabecular bone was demonstrated on bone biopsies analysed by three-dimensional micro-CT. The drug was shown to increase the number of trabeculae, the cortical thickness, and the total bone volume. The bone-forming activity of strontium ranelate was also demonstrated in comparative studies versus teriparatide and antiresorptive agents. In experimental studies the bone-forming effect of strontium ranelate leads to an increase in the bone callus volume and its maturation and, in turn, to an acceleration of the consolidation of the fracture and better implant osteointegration.
In conclusion, the mechanism of action of strontium ranelate, which inhibits bone resorption in favour of new bone formation, is able to counteract, in a physiological manner, the bone loss associated with advancing age. The net effect is an increase in bone mass, trabecular and cortical bone, which explains its anti-fracture efficacy. The drug’s ability to stimulate bone formation seems to unfold at the level of the callus allowing improved fracture healing and in the case of implants potential improvement of implant osteointegration.
PMCID: PMC3213810
7.  Fracture prevention in postmenopausal women 
Clinical Evidence  2010;2010:1109.
Introduction
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 78 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcitonin, calcium, calcium plus vitamin D, clodronate, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate.
Key Points
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years. About 13% of people die in the year after a hip fracture, and most survivors lose some or all of their previous independence.
Alendronate, risedronate, zoledronate, and parathyroid hormone reduce vertebral and non-vertebral fractures compared with placebo. Etidronate, ibandronate, pamidronate, and raloxifene reduce vertebral fractures, but have not been shown to reduce non-vertebral fractures. Raloxifene protects against breast cancer, but increases venous thromboembolic events and stroke compared with placebo. Strontium ranelate reduces vertebral and, to some extent, non-vertebral fractures. Calcitonin may reduce vertebral fractures over 1 to 5 years, but has not been shown to reduce non-vertebral fractures. Clodronate may reduce non-vertebral fractures at 3 years, but its effects on rate of vertebral fracture are unclear.
CAUTION: Hormone replacement therapy may reduce fractures, but it increases the risk of breast cancer and cardiovascular events. The risks of adverse effects of treatment are thought to outweigh the beneficial effects of hormone replacement therapy in prevention of fractures.
Combined calcium plus vitamin D, or vitamin D analogues alone, may reduce vertebral and non-vertebral fractures, but studies have given inconclusive results. Monotherapy with calcium or vitamin D has not been shown to reduce fractures.
We don't know whether multifactorial non-pharmacological interventions including environmental manipulation, or regular exercise, reduce the risk of fractures. Hip protectors may reduce the risk of hip fractures in nursing-home residents, but compliance tends to be low.
PMCID: PMC2907603
8.  Updated Recommendations for the Diagnosis and Management of Osteoporosis: A Local Perspective 
Annals of Saudi Medicine  2011;31(2):111-128.
Postmenopausal osteoporosis and osteoporosis in elderly men are major health problems, with a significant medical and economic burden. Although osteopenia and osteoporosis are more common locally than in the West, fracture rates are generally less than in Western countries. Vitamin D deficiency is common in the region and contributes adversely to bone health. Vitamin D deficiency should be suspected and treated in all subjects with ostopenia or osteoporosis. The use of risk factors to determine fracture risk has been adopted by the World Health Organization and many international societies. Absolute fracture risk methodology improves the use of resources by targeting subjects at higher risk of fractures for screening and management. The King Faisal Specialist Hospital Osteoporosis Working Group recommends screening for women 65 years and older and for men 70 years and older. Younger subjects with clinical risk factors and persons with clinical evidence of osteoporosis or diseases leading to osteoporosis should also be screened. These guidelines provide recommendations for treatment for postmenopausal women and men older than 50 years presenting with osteoporotic fractures for persons having osteoporosis—after excluding secondary causes—or for persons having low bone mass and a high risk for fracture. The Working Group has suggested an algorithm to use at King Faisal Specialist Hospital that is based on the availability, cost, and level of evidence of various therapeutic modalities. Adequate calcium and vitamin D supplement are recommended for all. Weekly alendronate (in the absence of contraindications) is recommended as first-line therapy. Alternatives to alendronate are raloxifene or strontium ranelate. Second-line therapies are zoledronic acid intravenously once yearly, when oral therapy is not feasible or complicated by side effects, or teriparatide in established osteoporosis with fractures.
doi:10.4103/0256-4947.77502
PMCID: PMC3102469  PMID: 21403406
9.  Strontium ranelate: a novel treatment for postmenopausal osteoporosis: a review of safety and efficacy 
Clinical Interventions in Aging  2006;1(4):367-375.
Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and hip fractures. Evidence for the safety and efficacy of strontium ranelate comes from two large multinational trials, the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Postmenopausal Osteoporosis) studies. The SOTI study evaluated vertebral fracture prevention in 1649 postmenopausal women with a mean age of 69 y. The subjects all had at least one previous vertebral fracture and a low spine bone mineral density (BMD) (equivalent to a Hologic spine T-score below −1.9). The strontium ranelate group had a 41% lower risk of a new vertebral fracture than the placebo group over the three-year study period (relative risk [RR]=0.59; 95% confidence interval [CI]: 0.48–0.73; p<0.001). The TROPOS study evaluated non-vertebral fracture prevention in 5091 postmenopausal women with a mean age of 77 y. The subjects were aged 74 y and over (or 70–74 y with one additional risk factor) and a low femoral neck BMD (equivalent to an NHANES III [Third National Health and Nutrition Examination Survey] T-score below −2.2). Over the three-year study period there was a 16% reduction in all non-vertebral fractures (RR=0.84; 95% CI 0.702–0.995; p=0.04) and a 19% reduction at the principal sites for non-vertebral fractures. The TROPOS study was not powered to investigate hip fracture risk. However, in a high risk group of women aged 74 y and over and with an NHANES III femoral neck T-score less than −2.4 there was a 36% reduction in hip fracture risk (RR=0.64; 95% CI: 0.412–0.997; p=0.046). The overall incidence of adverse events did not differ significantly from placebo and were generally mild and transient, the most common being nausea and diarrhea. Strontium ranelate is a useful addition to the range of anti-fracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and hip fractures in women aged 80 y and over.
PMCID: PMC2699648  PMID: 18046914
Strontium ranelate; osteoporosis treatment; postmenopausal women; vertebral fracture prevention; hip fracture prevention
10.  A review on strontium ranelate long-term antifracture efficacy in the treatment of postmenopausal osteoporosis 
Osteoporotic fractures are one of the major causes of increased morbidity and mortality in postmenopausal women and the overall aging population. One of the major issues in the management of postmenopausal osteoporosis is to find a safe and effective treatment in the long term (>3 years) to achieve and maintain a reduction in the risk of fracture. Strontium ranelate (PROTELOS®) is a relatively novel drug, currently approved in Europe for the treatment of postmenopausal osteoporosis. Strontium ranelate is the first agent of a new therapeutic class in osteoporosis, capable of both promoting bone formation and, to a lesser extent, inhibiting bone resorption. This uncoupling in bone turnover results in a net gain in bone mineral density (BMD), bone quality improvement and reduction in risk of vertebral and nonvertebral fractures, as initially demonstrated in the preplanned long-term registrative trials SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) at 5 years. Recently, open-label extensions of the SOTI and TROPOS trials up to 8 and, recently, 10 years have confirmed the sustained efficacy of strontium ranelate in increasing BMD, the long-term safety profile and the high compliance to treatment, independently from baseline BMD or other risk factors for osteoporotic fractures. Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.
doi:10.1177/1759720X13483187
PMCID: PMC3707343  PMID: 23858336
anabolic; antiresorptive; bone formation; bone mineral density; bone resorption; mineralization; safety; tolerability
11.  Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial 
PLoS Medicine  2008;5(10):1-12.
Background
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Conclusions
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Background.
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the ClinicalTrials.gov Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
doi:10.1371/journal.pmed.0050196
PMCID: PMC2566998  PMID: 18922041
12.  Five Years of Cenosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the First Two Years of the FREEDOM Extension 
The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a “virtual untreated twin” cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile. © 2012 American Society for Bone and Mineral Research
doi:10.1002/jbmr.1479
PMCID: PMC3415620  PMID: 22113951
BONE MINERAL DENSITY; BONE TURNOVER MARKERS; DENOSUMAB; FRACTURE; PIVOTAL FRACTURE TRIAL EXTENSION
13.  Strontium ranelate in postmenopausal osteoporosis treatment: a critical appraisal 
Osteoporosis is a progressive and debilitating disease characterized by a massive bone loss with a deterioration of bone tissues, and a propensity for a fragility fracture. Strontium ranelate is the first antiosteoporotic treatment that has dual mode of action and simultaneously increases bone formation, while decreasing bone resorption, thus rebalancing bone turnover formation. Strontium ranelate rebalances bone turnover in favor of improved bone geometry, cortical thickness, trabecular bone morphology and intrinsic bone tissue quality, which translates into enhanced bone strength. This review describes the mechanism of the strontium ranelate action and its effects on bone mineral density, bone turnover, and osteoporotic fractures. The efficacy of strontium ranelate in postmenopausal osteoporosis treatment to reduce the risk of vertebral and hip fractures has been highlighted in several randomized, controlled trials. Treatment efficacy with strontium ranelate has been documented across a wide range of patient profiles: age, number of prevalent vertebral fractures, body mass index, and a family history of osteoporosis. Because strontium ranelate has a large spectrum of efficacy, it can be used to treat different subgroups of patients with postmenopausal osteoporosis. Strontium ranelate was shown to be relatively well tolerated and the safety aspects were good. Strontium ranelate should be considered as a first-line treatment for postmenopausal osteoporotic patients.
PMCID: PMC2971725  PMID: 21072291
osteoporosis; strontium ranelate; therapy
14.  Reduction in Fracture Rate and Back Pain and Increased Quality of Life in Postmenopausal Women Treated with Teriparatide: 18-Month Data from the European Forsteo Observational Study (EFOS) 
Calcified Tissue International  2009;85(6):484-493.
The European Forsteo Observational Study was designed to examine the effectiveness of teriparatide in postmenopausal women with osteoporosis treated for up to 18 months in normal clinical practice in eight European countries. The incidence of clinical vertebral and nonvertebral fragility fractures, back pain, and health-related quality of life (HRQoL, EQ-5D) were assessed. Spontaneous reports of adverse events were collected. All 1,648 enrolled women were teriparatide treatment-naive, 91.0% of them had previously received other anti-osteoporosis drugs, and 72.8% completed the 18-month study. A total of 168 incident clinical fractures were sustained by 138 (8.8%) women (821 fractures/10,000 patient-years). A 47% decrease in the odds of fracture in the last 6-month period compared to the first 6-month period was observed (P < 0.005). Mean back pain VAS was reduced by 25.8 mm at end point (P < 0.001). Mean change from baseline in EQ-VAS was 13 mm by 18 months. The largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort. There were 365 adverse events spontaneously reported, of which 48.0% were considered related to teriparatide; adverse events were the reason for discontinuation for 79 (5.8%) patients. In conclusion, postmenopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18-month treatment period. This was associated with a clinically significant improvement in HRQoL. Safety was consistent with current prescribing information. These results should be interpreted in the context of the open-label, noncontrolled design of the study.
doi:10.1007/s00223-009-9299-6
PMCID: PMC2788127  PMID: 19823760
Osteoporosis; Teriparatide; Fracture; Back pain; Quality of life
15.  Pharmacological management of osteogenesis 
Clinics  2014;69(6):438-446.
Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases.
doi:10.6061/clinics/2014(06)12
PMCID: PMC4050321  PMID: 24964310
Antiresorptive Drugs; Bone Formation; Osteoblasts; Osteogenesis; RANKL Inhibitors
16.  Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis 
Osteoporosis International  2011;23(3):1115-1122.
Summary
In an open-label extension study, BMD increased continuously with strontium ranelate over 10 years in osteoporotic women (P < 0.01). Vertebral and nonvertebral fracture incidence was lower between 5 and 10 years than in a matched placebo group over 5 years (P < 0.05). Strontium ranelate's antifracture efficacy appears to be maintained long term.
Introduction
Strontium ranelate has proven efficacy against vertebral and nonvertebral fractures, including hip, over 5 years in postmenopausal osteoporosis. We explored long-term efficacy and safety of strontium ranelate over 10 years.
Methods
Postmenopausal osteoporotic women participating in the double-blind, placebo-controlled phase 3 studies SOTI and TROPOS to 5 years were invited to enter a 5-year open-label extension, during which they received strontium ranelate 2 g/day (n = 237, 10-year population). Bone mineral density (BMD) and fracture incidence were recorded, and FRAX® scores were calculated. The effect of strontium ranelate on fracture incidence was evaluated by comparison with a FRAX®-matched placebo group identified in the TROPOS placebo arm.
Results
The patients in the 10-year population had baseline characteristics comparable to those of the total SOTI/TROPOS population. Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years.
Conclusions
Long-term treatment with strontium ranelate is associated with sustained increases in BMD over 10 years, with a good safety profile. Our results also support the maintenance of antifracture efficacy over 10 years with strontium ranelate.
doi:10.1007/s00198-011-1847-z
PMCID: PMC3277702  PMID: 22124575
BMD; Long-term treatment; Osteoporotic fracture; Strontium ranelate
17.  Strontium ranelate in the treatment of knee osteoarthritis: new insights and emerging clinical evidence 
Osteoarthritis is a primary cause of disability and functional incapacity. Pharmacological treatment is currently limited to symptomatic management, and in advanced stages, surgery remains the only solution. The therapeutic armamentarium for osteoarthritis remains poor in treatments with an effect on joint structure, that is, disease-modifying osteoarthritis drugs (DMOADs). Glucosamine sulfate and chondroitin sulfate are the only medications for which some conclusive evidence for a disease-modifying effect is available. Strontium ranelate is currently indicated for the prevention of fracture in severe osteoporosis. Its efficacy and safety as a DMOAD in knee osteoarthritis has recently been explored in the SEKOIA trial, a 3-year randomized, double-blind, placebo-controlled trial. Outpatients with knee osteoarthritis, Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) of 2.5–5 mm received strontium ranelate 1 g/day (n = 558) or 2 g/day (n = 566), or placebo (n = 559). This sizable population was aged 62.9 years and had a JSW of 3.50 ± 0.84 mm. Treatment with strontium ranelate led to significantly less progression of knee osteoarthritis: estimates for annual difference in joint space narrowing versus placebo were 0.14 mm [95% confidence interval (CI) 0.05–0.23 mm; p < 0.001] for 1 g/day and 0.10 mm (95% CI 0.02–0.19 mm; p = 0.018) for 2 g/day, with no difference between strontium ranelate groups. Radiological progression was less frequent with strontium ranelate (22% with 1 g/day and 26% with 2 g/day versus 33% with placebo, both p < 0.05), as was radioclinical progression (8% and 7% versus 12%, both p < 0.05). Symptoms also improved with strontium ranelate 2 g/day only in terms of total WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score (p = 0.045), and its components for pain (p = 0.028) and physical function (p = 0.099). Responder analyses using a range of criteria for symptoms indicated that the effect of strontium ranelate 2 g/day on pain and physical function was clinically meaningful. Strontium ranelate was well tolerated. The observation of both structure and symptom modification with strontium ranelate 2 g/day makes SEKOIA a milestone in osteoarthritis research and treatment.
doi:10.1177/1759720X13500862
PMCID: PMC3791090  PMID: 24101948
joint space narrowing; osteoarthritis; strontium ranelate; symptoms; treatment
18.  The Prevention of Postmenopausal Osteoporotic Fractures: Results of the Health Technology Assessment of a New Antiosteoporotic Drug 
BioMed Research International  2014;2014:975927.
Objective. The Health Technology Assessment (HTA) approach was applied to denosumab in the prevention of osteoporotic fractures in postmenopausal women. Method. Epidemiological, clinical, technical, economic, organizational, and ethical aspects were considered. Medical electronic databases were accessed to evaluate osteoporosis epidemiology and therapeutical approaches. A budget impact and a cost-effectiveness analyses were performed to assess economic implications. Clinical benefits and patient needs were considered with respect to organizational and ethical evaluation. Results. In Italy around four millions women are affected by osteoporosis and have a higher risk for fractures with 70,000 women being hospitalized every year. Bisphosphonates and strontium ranelate are recommended as first line treatment for the prevention of osteoporotic fractures. Denosumab is effective in reducing vertebral, nonvertebral, and hip/femoral fractures with an advantage of being administered subcutaneously every six months. The budget impact analysis estimated a reduction in costs for the National Health Service with the introduction of denosumab. Furthermore, the economic analysis demonstrated that denosumab is cost-effective in comparison to oral bisphosphonates and strontium ranelate. Denosumab can be administered in outpatients by involving General Practitioners in the management. Ethical evaluation is positive because of its efficacy and compliance. Conclusion. Denosumab could add value in the prevention of osteoporotic fractures.
doi:10.1155/2014/975927
PMCID: PMC3932293  PMID: 24689066
19.  The Discovery and Development of Selective Estrogen Receptor Modulators (SERMs) for Clinical Practice 
Current Clinical Pharmacology  2013;8(2):135-155.
Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women’s health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer.
The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained.
In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.
doi:10.2174/1574884711308020006
PMCID: PMC3624793  PMID: 23062036
Arzoxifene; bazedoxifene; lasofoxifene; ospemifene; raloxifene; selective estrogen receptor modulator; tamoxifen.
20.  Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis 
Bisphosphonates are the leading drugs for the treatment of osteoporosis. In randomized controlled trials (RCTs), alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ) has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by epidemiologic studies or prospective RCTs.
PMCID: PMC2909499  PMID: 20668715
bisphosphonates; osteoporosis; safety
21.  Raloxifene for older women: a review of the literature 
Raloxifene is a non-steroidal selective estrogen-receptor modulator (SERM) which is used for prevention and treatment of postmenopausal osteoporosis. Raloxifene decreases the incidence of vertebral fractures by 30%–50% in postmenopausal women with osteoporosis but has not been shown to decrease the incidence of hip fractures or other non-vertebral fractures. At the present time, estrogen-replacement therapy and bisphosphonate treatment are the only medical treatments that are proven to prevent hip fractures with the exception of vitamin D and calcium replacement, which has been shown to prevent hip fractures in elderly individuals and nursing home residents. Raloxifene has been shown to have additive effects on bone turnover and bone mineral density (BMD) when used along with alendronate and teriparatide. Raloxifene could have a role in renal failure as it has been shown to increase BMD of the vertebra over 1 year of therapy. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. The increased incidence of venous thromboembolism is the main concern of raloxifene therapy and previous history of venous thromboembolism is a contraindication for use of raloxifene. Raloxifene has a role in treatment of vertebral osteoporosis in older women. The decision to use raloxifene should be based on evaluation of fracture risk and on potential other benefits than fracture reduction along with consideration of side effects.
PMCID: PMC2544368  PMID: 18488877
SERM; raloxifene; osteoporosis; women; fractures; old age
22.  Two Years of Denosumab and Teriparatide Administration in Postmenopausal Women With Osteoporosis (The DATA Extension Study): A Randomized Controlled Trial 
Lancet  2013;382(9886):50-56.
Context
Current osteoporosis medications increase bone mineral density (BMD) modestly and reduce, but do not eliminate, fracture risk. Attempts to improve efficacy by administering anabolic agents and bisphosphonates concomitantly have been unsuccessful. Conversely, 12 months of concomitant denosumab and teriparatide therapy increases BMD more than either drug alone.
Objective
The purpose of this study was to determine whether 24 months of combined denosumab and teriparatide will increase hip and spine BMD more than either individual agent.
Design
Preplanned continuation of the Denosumab and Teriparatide Administration (DATA) randomized controlled trial in which postmenopausal osteoporotic women received teriparatide (20 μg daily), denosumab (60 mg every 6 months), or both medications for 24 months.
Participants
Participants were 94 postmenopausal women with osteoporosis.
Outcome Measures
Lumbar spine, femoral neck, total hip, and distal radius BMD and serum markers of bone turnover were measured.
Results
At 24 months, lumbar spine BMD increased more in the combination group (12.9 ± 5.0%) than in either the teriparatide (9.5 ± 5.9%, P = .01) or denosumab (8.3 ± 3.4%, P = .008) groups. Femoral neck BMD also increased more in the combination group (6.8 ± 3.6%) than in either the teriparatide (2.8 ± 3.9%, P = .003) or denosumab (4.1 ± 3.8%, P = .008) groups. Similarly, total hip BMD increased more in the combination group (6.3 ± 2.6%) than in the teriparatide (2.0 ± 3.0%) or denosumab (3.2 ± 2.5%) groups (P < .001 for both). Although spine and hip BMD continued to increase in the second year in all groups, these year 2 increases did not differ among groups. Serum C-telopeptide and N-terminal propeptide of type 1 procollagen were equally suppressed in the denosumab and combination groups, whereas osteocalcin decreased more in the denosumab group than in the combination group, a difference that persisted, but lessened, in the second year of therapy.
Conclusions
Two years of concomitant teriparatide and denosumab therapy increases BMD more than therapy with either medication alone and more than has been reported with any current therapy. The combination of these agents may prove to be an important treatment option in patients at high risk of fracture.
doi:10.1016/S0140-6736(13)60856-9
PMCID: PMC4083737  PMID: 23683600
23.  Current medical treatment strategies concerning fracture healing 
Summary
The morbidity and socioeconomic costs associated with bone healing are considerable. A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, post-menopausal women, and in people with malnutrition.
The biologic process of fracture healing is complex and impacted by multiple factors. Some of them, such as the nutritional and health conditions, are patient-dependent, while others depend on the trauma experienced and stability of the fracture. Fracture healing disorders negatively affect the patient’s quality of life and result in high health-care costs, as a second surgery is required to stabilize the fracture and stimulate bone biology. Future biotechnologies that accelerate fracture healing may be useful tools, which might also prevent the onset of these disorders.
We list the characteristics of the drugs used for osteoporosis, but we point out in particular the use of strontium ranelate and teriparatide in our clinical practice in elderly patients, especially females, who reported fractures with risk of nonunion.
This medical treatment could impaired fracture healing however, most of the evidence is obtained in animal studies and very few studies have been done in humans. Thus one could hypothesize the possibility of a medical treatment both as a preventive and as support to the synthesis. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn.
A positive effect of osteoporosis treatments on bone healing is an interesting possibility and merits further clinical research.
PMCID: PMC3796998  PMID: 24133528
fracture healing; strontium ranelate; teriparatide
24.  Pharmacological agents and bone healing 
Osteoporosis is the most common alteration of bone metabolism. It derives from an increase in bone resorption with respect to bone formation and is characterized by microarchitectural alterations, decreased bone mass and increased risk of fracture. The coupling between bone formation and resorption is a fundamental concept in skeletal metabolism, and it explains how a certain amount of removed tissue can be replaced by the same amount of new bone. Various substances used to treat osteoporosis may also be used for orthopaedic conditions such as fracture healing, implant fixation, bone grafts and osteonecrosis. Fracture healing consists in the replacement of the lost bone by a tissue that has the same biomechanical properties as those preceding the fracture. The repair process is triggered by the local response to the tissue injury that damaged the continuity of bone. The duration of each phase of the healing process can vary significantly, depending on the site and characteristics of the fracture, on patient related factors and on the treatment choice. While most of the fractures heal with conventional treatment, they can also cause permanent damage and complications, especially in a certain kind of patients. Osteoporosis and old age may contribute in delaying or impairing the reparative process. In animal models the healing process is slower in older and/or ovariectomized animals. Biomechanical tests have also shown that bone strength is compromised in human osteoporotic cadaver bone. The same problems were highlighted in the surgical treatment of fractures in osteoporotic patients. Mainly in the treatment of hip fractures there is an increased risk of cut-out, re-fractures and implant failure in patients with osteoporosis. Preclinical studies have shown that certain pharmacological agents (bisphosphonates, strontium ranelate, teriparatide) may enhance osseointegration and stimulate reparative processes. They may be administered systemically and/or used locally at the fracture site on the implant surface. The aim of fracture treatment is to restore bone biomechanical properties and to allow restoring normal function at the affected site. If the new pharmacological approaches could be translated into clinical benefit and offered to patients with osteoporosis or other factors that put at risk the process of healing (subjects with severe loss of substance or fractures at high risk of complications), they could represent a valuable aid in the treatment of fractures.
PMCID: PMC2781222  PMID: 22461164
fracture healing, bone remodeling, osteoporosis treatment.
25.  Cost-effectiveness of strontium ranelate in the treatment of male osteoporosis 
Osteoporosis International  2013;24(8):2291-2300.
Summary
The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered a cost-effective strategy compared with no treatment for the treatment of osteoporotic men from a Belgian healthcare payer perspective.
Introduction
This study was conducted to estimate the cost-effectiveness of strontium ranelate in the treatment of osteoporotic men.
Methods
A previously validated Markov microsimulation model was adapted to estimate the cost (€2,010) per quality-adjusted life-year (QALY) gained of strontium ranelate compared with no treatment. Similar efficacy data on lumbar spine and femoral neck bone mineral density (BMD) between men with osteoporosis at high risk of fracture (MALEO Trial) and postmenopausal osteoporotic women (pivotal SOTI, TROPOS trials) supports the assumption, in the base-case analysis, of the same relative risk reduction of fractures in men as for women. Analyses were conducted, from a Belgian healthcare payer perspective, in the population from the MALEO Trial who is a men population with a mean age of 73 years, and BMD T-score ≤−2.5 or prevalent vertebral fracture (PVF).
Results
In the MALEO population, strontium ranelate compared with no treatment was estimated at €49,798 and €25,584 per QALY gained using efficacy data from the intent-to-treat analysis and the per-protocol analysis including only adherent patients, respectively. In men with a BMD T-score ≤−2.5 or with PVF, the cost per QALY gained of strontium ranelate fall below thresholds of €45,000 and €25,000 per QALY gained based on efficacy data from the entire population of the clinical trial and from the per-protocol analyses, respectively.
Conclusions
The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered cost-effective compared with no treatment for male osteoporosis.
doi:10.1007/s00198-013-2272-2
PMCID: PMC3706715  PMID: 23371359
Cost-effectiveness; Fractures; Men; Osteoporosis; Strontium ranelate

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