Osteoporosis is a bone disease characterized by low bone mass and deterioration of bone tissue resulting in compromised bone strength and increase in risk of fracture, particularly of the hip, spine and wrist. In adults, a normal process called resorption takes place where there is a daily removal of small amounts of bone mineral, which must be balanced by an equal deposition of new mineral if bone strength is to be preserved. When this equilibrium tips toward excessive resorption, our bones weaken (osteopenia) and over time can become brittle and prone to fracture (osteoporosis) (Sipos, Pietschmann, Rauner, Kerschan-Schindl, & Patsch, 2009). This continual resorption and redeposition of bone mineral, or bone remodeling, is intimately tied to the pathophysiology of osteoporosis. Osteoporosis can be classified as primary and secondary. Primary osteoporosis is defined as the loss of bone mass related to the ageing process, including estrogen deficiency due to menopause and secondary osteoporosis is attributed to concomitant diseases such as celiac disease, hemophilia, renal disease or medications such as glucocorticoids, anticoagulants, chemotherapeutic drugs, etc (Sipos et al., 2009).
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Epidemiology of Osteoporosis
As the population ages, Osteoporosis continues to be a major public health issue. Currently it is estimated that over 200 million people worldwide suffer from this disease. Today, there are approximately 2 million Canadians (one in four women and one in eight men over the age of 50) who suffer from Osteoporosis (Rosen & Drezner, 2010). From a financial standpoint, the cost of treating Osteoporosis is estimated to be $1.9 billion each year in Canada alone where long term, hospital and chronic care account for the majority of these costs (Osteoporosis Canada, 2011). Given the increasing proportion of older people in the population, these costs will likely rise.
Pathophysiology of Osteoporosis
The long bones (e.g. femur, humerus) are tubular in shape, with a strong outer shell- the "cortical layer", surrounding a softer, spongier core called "trabecular" bone (Kanis et al., 2002). The combination of these two types makes these bones strong and light, but flexible enough to absorb the stress from high impact exercises without breaking. The vertebrae are similarly constructed, with a thick cortical layer surrounding sheets of trabecular bone. The balance between bone resorption and bone deposition is determined by the activities of two principle cell types, "osteoclasts" and "osteoblasts". Osteoclasts contain highly active ion channels in the cell membrane that pump protons into the extracellular space, thus lowering the pH in their own microenvironment, and eventually dissolves the bone mineral (Kanis et al., 2002). Osteoblasts however are able to lay down new bone mineral. The balance between the activities of these two cell types governs whether bone is made, maintained, or lost. Typically, in the bone remodeling cycle, osteoclasts are activated first, leading to bone resorption followed by a brief "reversal" phase, during which the resorption "pit" is occupied by osteoblasts precursors. Bone formation, then begins as progressive waves of osteoblasts form and lay down fresh bone matrix (Bartl & Bartl, 2011). Hormones play the role of being the most crucial modulators of bone formation. It is well established that estrogen, parathyroid hormone, and testosterone are essential for optimal bone development and maintenance (Bartl & Bartl, 2011). Taking these hormones in factor along with the osteoblasts/osteoclasts equilibrium, if the net bone loss is much more significant than net bone gain, osteoporosis develops.
Diagnosing osteoporosis remains a serious challenge because of the lack of symptoms in the absence of fractures, which has resulted in suboptimal level of diagnosis, treatment and unnecessarily high rates of fractures. Medical history that is positive for risk factors should prompt further investigations to diagnose osteoporosis by measuring bone mineral density using dual-energy x-ray absorptiometry (DXA). Recommendations from the 2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada states that the recommended elements in the History and Physical Examination should identify future fractures and fall risks such as prior fragility fractures, parental hip fracture, glucocorticoid use, current smoking, high alcohol intake, rheumatoid arthritis, and inquire about falls in the previous 12 months, gait and balance, accurate height and weight measurements (Bartl & Bartl, 2011). Other risk factors that have been associated with osteoporosis include: breast-fed infants, older adults (>65), obese, limited sun exposure, dark-skin, fat malabsorption issues, Caucasian race, adult history of fractures, and poor eyesight.
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Treatment and Management of Osteoporosis
Traditionally, the mainstay of the treatment of Osteoporosis includes non-pharmacological and pharmacological therapies. Non-pharmacological therapy includes 1200mg of elemental calcium and 800IU of vitamin D daily with lifestyle modifications that include weight loss, smoking cessation, and counseling on fall prevention and avoidance of heavy alcohol (Delmas, 2002). In addition to non-pharmacological therapy, pharmacological interventions such as bisphosphonates are recommended for those with established osteoporosis (T â‰¤ -2.5) or a fragility fracture (hip or vertebral) (Delmas, 2002). Recent literature points to the fact that combined therapy using bisphosphonates, calcium and vitamin D is the most effective treatment for osteoporosis rather than a single therapy (Bartl & Bartl, 2011).
Vitamin D, its deficiency and the link to Osteoporosis
There are two main forms of the fat-soluble vitamin D: Vitamin D3 or cholecalciferol, which is synthesized in the skin following exposure to sunlight or ultraviolet light and from nutritional sources like fatty fish, and vitamin D2, ergocalciferol, which can be obtained from irradiating plants or other foods (Sipos et al., 2009). Vitamin D3 is hydroxylated in the liver into 25-hydroxyvitamin D3 (25(OH) D) and eventually in the kidneys into 1, 25 dihydroxyvitamin D3 (1, 25 (OH) 2D), which remains as the active metabolite that stimulates calcium absorption into the gut (Sipos et al., 2009). This active metabolite, 1, 25 (OH) 2D enters the cells and binds to a vitamin D receptor and allows calcium to enter the cells through membrane proteins. The 1, 25(OH) 2D eventually has its effect on targets like bone, intestine, and kidney and stimulates calcium transport from these organs to the blood. However, the production of 1, 25(OH) 2D is stimulated by parathyroid hormone (PTH) and direct and indirect negative feedback via calcium exist to regulate the production of this metabolite.
Figure 1: Structure of Vitamin D and its numbering system (DeLuca, 2004).
Vitamin D aids the absorption of calcium from the intestinal tract by stimulating the synthesis of calcium-binding protein in the intestinal mucous membrane. It also aids the resorption of phosphate in the renal tube. Vitamin D mobilizes phosphate from the bone to maintain serum phosphate levels, and stimulates the active phosphate transport.
Figure 2: Schematic diagram of the different functions of vitamin D. Photo credit from medscape.com
The deficiency of this hormone creates a deficient deposition of hydroxyapatite in the bones. This is due to inadequate absorption of calcium from the intestinal tract, and from the retention of phosphorus in the kidney. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of osteoporosis in the elderly (Lau & Baylink, 1999). This abnormality, then leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. In population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward and the cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency (Lau & Baylink, 1999). There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)(2)D(3) resulting from decreased renal production; and (3) resistance to 1,25(OH)(2)D(3) action owing to decreased responsiveness in target tissues (Lau & Baylink, 1999). The cause for the resistance to 1, 25(OH)(2)D(3) could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and osteoporosis (Lau & Baylink, 1999). To combat, there are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)(2)D(3) deficiency/resistance requires active vitamin D analog therapy to correct the high serum PTH and the Ca malabsorption (Lau & Baylink, 1999).
Native Vitamin D versus Vitamin D Analogues
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Excessive supplementation of vitamin D can cause hypercalcemia, which can lead to vascular and tissue calcification that can damage the heart, blood vessels and the kidneys. As a result, recent studies have considered synthetic vitamin D analogues such as alfacalcidol and calcitriol in order to avoid the harmful effects of excessive supplementation with native vitamin D. In vitamin D sufficient patients, native vitamin D does not provide any benefits. In addition, in patients with vitamin D hormone deficiency, or vitamin D hormone receptor deficits in quantity and quality, they are found to be resistant to native vitamin D. Unlike native vitamin D that is mainly found in the serum, vitamin D analogues are a prodrug of native vitamin D and increase in concentration on the target organs such as bones for both vitamin D depleted and replete patients. As a result they bypass the kidney's negative feedback loop and result in a higher concentration without causing hypercalcemia and hyperparathyroidism (Kanis et al., 2002). However, there is generally a suboptimal appreciation by both physicians and patients of the importance of vitamin D for maintenance of bone health as reflected in the low number of patients who reported regularly taking these supplements (Chan, Scott, & Sen, 2010). Recently in 2009, in an online survey study conducted at Spaulding Rehabilitation Hospital in Boston, USA, only 54% of practitioners (physicians, physician assistants and nurse practioners) were prescribing vitamin D for the treatment of osteoporosis (Morse et al., 2009).
Capstone Objective and PICO Question
The lack of the use of vitamin D could potentially be due to a lack of understanding of how vitamin D functions and when it is useful. This paper will focus on 5 studies that were recently published that help to understand the difference between native vitamin D and vitamin D analogues. Specifically, in the setting of patients with osteoporosis, does the supplementation of Vitamin D analogues with bisphosphonates help to reduce the incidence of fractures more than native Vitamin D? A deeper understanding of when to use what kind of vitamin D should increase its usage to allow for its benefits for the patients suffering from this illness.
2.1 Strategy for Accessing Evidence Based Medicine:
I conducted a systematic review of all English articles using MEDLINE (Ovid, PubMed) from January 1980 to March 2011. I used Medical Subject Heading (MeSH) terms which included trials (randomized controlled trial, controlled clinical trial, random allocation, double blind method, single-blind method or uncontrolled trials), meta analysis, vitamin D (cholecalciferol, ergocalciferol, 25-hydroxyvitamin D), vitamin D analogs (alfacalcidol, calcitriol), osteoporosis (primary osteoporosis, secondary osteoporosis) fractures (hips fractures, femoral neck fractures, femoral fractures, humeral fractures, radius fractures, or tibial fractures), humans, elderly, falls and bone mineral density.
3.1 Justification of the papers:
The following papers include 2 meta-analyses and 3 randomized controlled trials. I decided to include meta-analyses because they provide a wealth of information relating to my PICO question. Since they study the derivation and statistical testing of overall factors / effect size parameters in related studies, it usually carries a higher statistical power to detect an effect. The two meta-analyses include only methodologically sound studies, giving us a best evidence meta-analysis since it combines several studies and will consequently be less influenced by local findings than single studies will be. The 3 randomized controlled trials (RCT) included were outside the studies incorporated in the meta-analysis and also provided good evidence to answer our PICO question. Although these are single studies, the RCTs are considered by most to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because they can reduce false causality and bias.
3.2 Evidence-based Medicine
Paper 1:"Differential Effects of D-Hormone Analogs and Native Vitamin D on the Risk of Falls: A Comparative Meta-Analysis" by Richy et al., 2007.
Summary- The aim of this paper was to compare the antifall efficacy of native vitamin D to its hydroxylated analogs alfacalcidol and calcitriol using 11 randomized and double-blind and 3 randomized studies ( 21, 268 subjects) from January 1995- May 2007.
Results- The results from this study are valid for our clinical question since this study was interested in understanding the role of native vitamin D versus vitamin D analogues in the prevention of falls. In addition, all the patients that started the trials were properly analyzed and accounted for at the end of the trials as well, with the percent drop-out rates calculated. For 11 trials, the patients and their clinicians were kept blind with regards to whether they were being treated with vitamin D, vitamin D analogue or a placebo. The population of people included in the 14 trials were similar in age (mean age: 78.3 Â±4.8) and included both men and women and the median duration was 12 months. Using the data, the relative risk (RR) for falling when allocated to active treatment was 0.94 (95% confidence interval (CI) 0.90-0.99) compared to placebo. Vitamin D analogues did provide a statistically significant lower level of risk (RR=0.79, CI 0.64-0.96) when compared to native vitamin D (RR=0.95, CI 0.87-1.01) with the intergroup difference P=0.049. The number needed to treat (NNT), which is a measure of the number of patients who need to be treated in order to prevent one fall was calculated to be 12 for vitamin D analogue and 52 for native vitamin D.
As with any study, there are limitations. The assessment of falls may be biased on average given that recall bias is frequent among elderly men and women. In additions, the results from this study use population that is not necessarily affected with osteoporosis, which makes it slightly hard to exploit these results and apply them to our population that has osteoporosis. However, given the prevalence of this illness and the age of subjects, it is possible that a significant part of the population that was studied by this group could have osteoporosis. In our case, vitamin D analogue treatment from this study can be quite feasible for our population with osteoporosis as well. In addition, there are no potential harms from this therapy that outweigh the benefits. The likely superiority of vitamin D analogues compared to native vitamin D relies on the finding that the metabolic pathway of vitamin D hormone analogues bypasses the renal feedback regulation, resulting in higher concentration of D-hormone at the receptors of target organs (Sipos et al., 2009).
Paper 2: "Vitamin D Analogues versus Native Vitamin D in Preventing Bone Loss and Osteoporosis-Related Fractures: A Comparative Meta-analysis" by Richy et al., 2005.
Summary- The aim of this study was compare the effect of native vitamin D to its hydroxylated analogues alfacalcidol and calcitriol in preserving bone mineral density (BMD) in both primary and corticosteroid-induced osteoporosis using 32 randomized, controlled, double-blind trials from January 1985- January 2003.
Results- In this study, clinical trials were considered eligible if subjects were (1) pre- or post menopausal women, men aged >50 years or patients requiring corticosteroids daily (2)randomized to take native versus vitamin D analogue (3) and double-blinded with a minimal study duration of 6 months with BMD outcomes assessed using dual X-ray absorptiometry (DXA). Study heterogeneity was kept in mind to ensure that all groups in the clinical trials were similar to each other and sensitivity analyses were performed by analyzing the impact of the following covariant on global estimates: age, sex ratio, compound, dose, study design, study duration, year of publication, impact factor of journal and the dropout rates. Therefore, aside from the intervention, all groups were treated equally. The study demonstrated that the two vitamin D analogues, alfacalcidol and calcitriol appeared to exert a higher preventative effect on bone loss and fracture rates than compared to native vitamin D and placebo. It was found at a median 24 month duration that alfacalcidol and calcitriol versus placebo had a significant preventative effect on hip and lumbar bone loss with an effect size (ES) of 0.36 (p<0.0001) compared to ES= 0.17 (p<0.0005) for native vitamin D versus placebo. Additionally, when comparing the adjusted global relative risks for fractures, alfacalcidol and calcitriol provided a more marked preventative efficacy against fractures with a rate difference (RD) of 10% (CI= -2 to 17) compared to native vitamin D with an RD of 2% (CI=1-2). In patients treated with corticosteroids, placebo-comparison studies showed that vitamin-D analogs and native had similar effects on BMD (ES 0.38 vs 0.41, p=0.88). Effects were not significantly different with regard to spinal BMD, and neither D analogs nor native vitamin D significantly prevented fractures. However, in head-to-head studies comparing vitamin-D analogs and native vitamin D in this population, the analogs were significantly better at preserving femoral-neck BMD and at preventing spinal fractures, favoring D-analogues for femoral neck BMD: ES=0.31 (p<0.02) and spinal fractures RD=15% (CI= 6.5-25). Therefore, this study established the superiority of D-analogues in preventing bone loss and fractures in primary, post-menopausal osteoporosis, but seems to be unclear for corticosteroid induced osteoporosis.
Paper 3: "Superiority of a Combined Treatment of Alendronate and Alfacalcidol Compared to the Combination of Alendronate and Plain Vitamin D or Alfacalcidol Alone in Established Post-menopausal or Male Osteoporosis" by Ringe, J.D. et al., 2007.
Summary- The purpose of this open randomized controlled trial was to compare the efficacy and safety of a treatment with either alfacalcidol alone (group A) or alendronate with native vitamin D ( group B) in patients with osteoporosis or vitamin D analogue (alfacalcidol) and a bisphosphonate (alendronate) (group C) combined.
Results- In this 2- year study, 90 patients were randomly organized using the inclusion criteria of (1) established postmenopausal and male osteoporosis (2) No secondary osteoporosis (3)BMD L2-L4 <3.0 T score (4) BMD total hip <2.5 T score (5) One or more prevalent vertebral fracture (5) No bisphosphonate, fluoride, or PTH treatment in the last 6 months. BMD was measured using DXA at the beginning, and after 12 and 24 months. ES measurement for the group C versus group A was 0.9322 with a CI of 0.7740 (p<0.0001) and versus group B was 0.8511, CI= 0.6959 (p<0.0001). This large superiority (ES>0.70) of the combination therapy of alfacalcidol and alendronate versus both group A and B was also resonant when the number of patients with new fractures (vertebral and non-vertebral) was examined after 24 months. ES of group C versus group A was 0.6167, CI=0.5253 (p<0.02) and versus group B was 0.6333, CI=0.5379 (p<0.01). The results from this study are relevant to our study population because they include patients with osteoporosis and also identify that a combination therapy of alendronate and alfacalcidol is much more noteworthy than monotherapy alone. There are however, significant limitations to this study as well. Several studies have concluded that the results of unblinded RCTs tend to be biased toward beneficial effects only and it possible that this study could suffer from this as well as observer bias.
Paper 4: "Effects of Combined Treatment with Alendronate and Alfacalcidol on Bone Mineral Density and Bone Turnover in Postmenopausal Osteoporosis: A two-years, randomized, multiarm, controlled trial" by One, K. et al., 2007.
Summary- The aim of this prospective, randomized, single-blind, controlled trial of 24 months' duration study was to evaluate 197 postmenopausal women with osteoporosis to compare the efficacy of Alendronate + Alfacalcidol + calcium (group A), Alendronate + Calcium (group B), Alfacalcidol + calcium (group C), or Calcium alone (group D), on bone mineral density and bone metabolism markers. BMD was measured at the lumbar spine (L2-L4) and the femur neck using dual energy x-ray absorptiometry (LUNAR DPX) at baseline and after 12 and 24 months. The 5% level of statistical significance has been used for all assessments.
Results- Subjects were randomized to groups A, B, C and D. At 2-years, and at the lumbar level, the highest significant gain in bone mass was seen for group A +8.4%, followed by group B +6.4%, and group C +2.3%, while a significant decrease was seen among subjects from group D -2.5%. A similar pattern was observed at the femoral neck level, with gains ranging from +5.3% for group A, +3.8% for group B, +1.2% (NS) for group C, and -6.4% for group D. Data from this randomized controlled trial suggested a higher efficacy in increasing bone mineral density and a similar tolerance of combined therapy with Alendronate and Alfacalcidol compared to Alfacalcidol alone, and to Alendronate as a consistent trend. Importantly, the combined therapy resulted in lower rates of hypercalciuria, hypercalcemia, and hypocalcemia compared to monotherapies. However, limitations of this study include compliance. It was poorly recorded, although this parameter is recognized as a major determinant of treatment efficacy. Nevertheless, further large, double-blind, dose-ranging studies in postmenopausal osteoporosis and subjects with increased risk of falls are still required to confirm the synergistic efficacy of Alendronate in combination with Alfacalcidol in the reduction of falls and vertebral, non-vertebral fractures.
Paper 5: "Prevention and treatment of glucocorticoid-induced osteoporosis with
active vitamin D3 analogues: a review with meta-analysis of randomized
controlled trials including organ transplantation studies" by de Nijs, R. N. J. et al., 2004.
Summary- The aim of this review with meta-analysis was to determine if there is a rationale to use activated forms of vitamin D3 to treat or prevent glucocorticoid-induced osteoporosis, and to compare the eï¬€ect of active vitamin D3 metabolites with native vitamin D and/or calcium, placebo, and no treatment.
Results- The assignment of the patients to the different groups was randomized, although they were not necessarily blinded. Selection criteria and group heterogeneity was kept in account before the start of the trial to ensure that the groups did not differ much. Concerning the effect on bone mineral density, the pooled effect size of active vitamin D3 analogues compared with no treatment, placebo, plain vitamin D3 and/or calcium was 0.35 (95% confidence interval (CI) 0.18, 0.52). Compared with bisphosphonates, the pooled effect size was -1.03 (95% CI -1.71, -0.36). However, the pooled estimate of the relative risk for vertebral fractures of active vitamin D3 analogues compared with no treatment, placebo, plain vitamin D3 and/or calcium was 0.56 (95% CI 0.34, 0.92) and compared with bisphosphonates it was 1.20 (95% CI 0.32, 4.55). Active vitamin D3 analogues decrease the risk of vertebral fractures and preserve bone during glucocorticoid therapy more effectively than no treatment, placebo, plain vitamin D3 and/or calcium, but bisphosphonates are more effective in preserving bone mineral density. In addition, there do not seem to be any documented cases of potential harm with vitamin D analogue therapy that would outweigh its benefits. In summary, this study indicated that active vitamin D3 analogues are eï¬€ective in preserving bone and reduces the risk of vertebral fractures during treatment with GCs.
In conclusion, our PICO question of whether vitamin D analogues in combination with bisphosphonates were superior to native vitamin D was addressed. Literature eludes that vitamin D analogues are better than native vitamin D treatment regardless of whether in combination with bisphosphonates or not. The papers that were selected were bias free and most included some form of inclusion criteria. Our population is similar in terms of age from the ones studied in these papers that the results would be highly applicable. Of course, there are still numerous differences such as time, culture, and stage of illness that differ from one study to the next which can affect the results and those differences must still be kept in mind. Overall, this study has been able to compare different modalities of fracture risk reduction that would be highly applicable in our population.