Since the publication of the 2002 edition of the Canadian Osteoporosis Guidelines, there have been further advances in the prevention and treatment of osteoporosis and osteoporotic fractures internationally, for example, reduced bone mineral density is only one of the many factors contributing to osteoporotic fractures, and anti-osteoporosis treatment is no longer the sole focus, but rather the prevention of osteoporotic fractures and their adverse consequences.
Clinical findings suggest that risk factors for osteoporotic fractures do not correlate with bone density, so a comprehensive assessment must be performed to determine the absolute risk of osteoporotic fractures and to develop a basic treatment plan. Surveys have shown that a significant proportion of patients with fractures are not able to be properly evaluated and treated. In order to fill this gap, the 2010 edition of the guidelines focuses on the assessment and treatment of those at high risk for fragility fractures over the age of 50, as well as developing a program to assess the risk of fracture over the next 10 years for holistic management.
[Severity and importance].
Studies have found that osteoporotic fractures can directly contribute to increased morbidity and mortality, as well as trigger chronic pain, length of hospital stay, and corresponding increases in medical expenditures. osteoporotic fractures account for 80% of fractures in menopausal women over the age of 50. Among them, the risk of death after hip fracture and vertebral fracture are both higher. In comparison, mortality and length of hospital stay after fracture were greater in men than in women.
With such a high incidence and risk of osteoporotic fractures, less than 20% of women and less than 10% of men have received preventive treatment for osteoporotic fractures. Such statistics are in stark contrast to heart disease – 75% of patients with a history of heart attack are on beta-blockers for prophylactic treatment.
[Scope of the guideline].
The target population of this guideline is middle-aged and older adults over 50 years of age, as the occurrence of osteoporotic fractures is mainly concentrated in this age group. This guideline reviews the extensive literature on this group, including the applicability to children and young adults, as well as high-risk patients who have undergone transplantation, and has been well studied.
Birth of the Guidelines
The guideline was developed following the “assessment-survey-evaluation” approach. We interviewed a large number of primary care physicians, osteoporosis patients, osteoporosis specialists, imaging specialists, orthopedic specialists, and health policy decision makers to obtain their opinions. We systematically reviewed a large body of relevant literature, focusing on updating knowledge in two areas: assessment of osteoporotic fracture risk, and treatment.
We formed the Best Practice Guidelines Committee (BPGC), with members drawn from experts and academics across Canada. We searched seven major electronic databases and did an extensive literature review to compile and study all the literature on osteoporotic fracture risk assessment from 1990 to 2009, a total of 35 articles. We performed a systematic review of treatments for osteoporosis published before 2008, including 76 randomized trials and 24 Meta-analyses, and 30 randomized controlled studies. The data sources we referenced were all relevant literature published up to September 19, 2010.
[Clinical Recommendations
▪ Who should be evaluated for osteoporosis and osteoporotic fracture risk?
We believe that all middle-aged people over the age of 50 should be evaluated for risk of osteoporosis and osteoporotic fracture to clarify the magnitude of risk.
1. Risk assessment is strongly recommended for those over 50 years of age and with a previous history of osteoporotic fracture (recommended intensity: level A).
■ How should the risk of osteoporosis and osteoporotic fracture be assessed?
Extensive screening for reduced bone density, history of trauma such as falls, and other associated risk factors, especially previously missed vertebral compression fractures, is performed through detailed history taking and relevant ancillary examinations.
1, Measure height and assess for possible vertebral fractures annually (recommended intensity: Grade A).
2. Determine whether any falls have occurred in the past year, including the ability to get out of a chair without relying on the arms, and if a fall has occurred, a full risk assessment should be performed (recommended intensity: Level A).
▪ What tests should be performed in sequence?
For the vast majority of patients with osteoporosis (T value > -2.5), further ancillary tests are required. Studies have found a twofold increase in the incidence of fractures in those with increased bone turnover markers, which does not correlate clearly with BMD. However, whether or not bone conversion markers can be used to assess an individual’s risk of fracture remains to be further investigated.
1, Exclusion of secondary factors contributing to osteoporosis by a series of biochemical tests is a prerequisite for clinical assessment (recommended strength: level D).
2. Serological 25-OH vitamin D screening is recommended for individuals who are ready to receive anti-osteoporosis medication, individuals with recurrent osteoporotic fractures, individuals who continue to have decreased bone mineral density despite anti-osteoporosis treatment, and individuals who have other complications of their own that affect vitamin D absorption and activity (strength of recommendation: level D).
3. Serological 25-OH vitamin D screening should be performed 3 to 4 months after vitamin D supplementation and can be discontinued once levels of 75 nmol/L or higher are reached (recommended intensity: level B).
4. For healthy adults, such as individuals without osteoporosis or various complications affecting vitamin D absorption and activity, the risk of vitamin D deficiency is generally low and serological 25-OH vitamin D testing is not recommended (recommended intensity: level D).
Compared to other types of bone densitometry, dual-energy x-ray bone densitometry is most suitable for the evaluation of vertebral fractures.
Non-traumatic vertebral fractures are defined as vertebral endplate destruction with vertebral height loss of 25% or more visible on lateral X-rays. The risk of future vertebral fracture in this population is five times greater than normal.
1. If there is clinical evidence that suggests the possibility of vertebral fracture, a lateral x-ray of the thoracic and lumbar spine or a vertebral fracture assessment by dual-energy x-ray bone densitometry is recommended (recommended strength: Grade A).
▪ How to assess the risk of osteoporotic fracture in the next 10 years?
Currently, the two most commonly used systems for assessing the 10-year risk of various osteoporotic fractures, such as hip fractures, vertebral fractures, forearm fractures or proximal humerus fractures, are: the modified CAROC (Canadian Osteoporosis and Canadian Imaging Society) system and the fracture risk assessment system proposed by the WHO (World Health Organization). Both systems use the BMD value of the femoral neck or its T value as the basic reference. The 2005 version of the CAROC system, which was based on relevant Swedish statistics, has been replaced by the 2010 Canadian version of the CAROC system.
The CAROC system is based on the risk of osteoporotic fractures in people over 50 years of age over the next 10 years and is divided into three groups: a low risk group (<10% incidence), an intermediate group (10%-20%) and a high risk group (>20%). The original risk classification was based on age, sex and femoral neck BMD values (provided by the National Nutrition and Health Survey III) for white women as the basic reference.
The main independent risk factors that are now clear include: people over 40 years of age with a previous history of osteoporotic fracture, and long-term glucocorticoid use (prednisolone 7.5 mg or more daily for at least 3 months in the past 1 year). The presence of either of these factors could lead to an increase in an individual’s risk of osteoporotic fracture by one level (from the low- to intermediate-risk group or from the intermediate- to high-risk group). Individuals with both factors should be considered to be at high risk for osteoporotic fracture, regardless of their BMD values.
The WHO risk assessment system uses several parameters including sex, age, BMI, history of previous fractures, parental history of hip fracture, history of long-term glucocorticoid use, rheumatoid arthritis (a minor factor in osteoporosis), history of smoking, history of alcohol abuse (more than 3 drinks per day), and BMD values of the femoral neck. the WHO fracture risk assessment system fully takes into account the factors of BMD, and those that do not take into account BMD or rely solely on bone density, has a clear advantage over assessment systems that do not. The initial risk assessments of both systems did not address BMD in the lumbar spine, but the fracture risk was somewhat underestimated when T values in the lumbar spine were lower than in the hip.
The prediction of osteoporotic fracture is essentially the same for both systems. the WHO system is based on several clinical risk factors, is more comprehensive, and can be used even without BMD findings, but requires the use of relevant software, an online network, or some written charts. In contrast, the 2010 version of CAROC involves fewer parameters but is much easier to use.
The risk assessments made by both systems are highly consistent (about 90%), with differences usually due to one or more factors that are addressed in the WHO assessment tool but not in the 2010 version of CAROC, such as parental history of osteoporotic hip fracture, history of smoking, history of alcohol abuse, and history of rheumatoid arthritis. The choice of instrument depends on personal preference or convenience.
Neither assessment system is applicable to people under the age of 50. In general, the presence of an osteoporotic fracture in a person under 50 years of age means that the cause is likely to be more complex, and its evaluation and treatment will usually require access to a specialist. In addition, the assessment results obtained by both systems reflect only the theoretical risk at the beginning of treatment, without a corresponding reduction in risk after treatment.
Absolute risk factors for fracture, such as age, BMD, previous history of fragility fracture and glucocorticoid use, should be included as basic tests (recommended strength: A).
2. The CAROC 2010 version system and the Canadian version of the WHO system, both of which have been fully validated in Canada, can be used (strength of recommendation: level A).
3.If the purpose is to report bone density values, the CAROC 2010 version system is currently the preferred national risk assessment system (recommended strength: level D).
4, Both systems use the femoral neck T-value (using the statistics provided by the National Nutrition and Health Survey Report III for white women as the reference value) to calculate the risk of future osteoporotic fractures (recommended strength: level D).
5, Individuals with a vertebral or total hip T value ≤ -2.5 should be considered to be at least in the intermediate risk group (recommended intensity: Level D).
6, A history of multiple prior fractures implies greater risk. In addition, individuals with previous hip fractures and vertebral fractures are at greater risk than individuals with fractures at other sites (recommended intensity: level B).
What treatments are available?
■ Exercise and fall prevention
Exercise can significantly improve the quality of life for people with osteoporosis, especially for improving function, relieving pain, and improving muscle strength and balance. Although there is a lack of strong evidence that exercise reduces the incidence of fractures, it has been shown that moderate to light walking exercise can significantly reduce the risk of hip fractures.
The Home Safety Assessment (HSA) is only indicated for people with severe vision loss or the presence of other risk factors for falls. The study found that the probability of falling was greatly reduced after an individual’s first cataract extraction, but interventions to reduce the probability of falling did not reduce the incidence of fracture. Hip protectors significantly reduced the incidence of hip fractures in patients receiving long-term care in Canada, but the effect was not significant in community residents, possibly related to their poor compliance.
1. Exercise, including resistance training, should be individualized and tailored to the age and function of the individual; weight-bearing aerobic exercise is appropriate for patients with osteoporosis and those at risk for osteoporosis (recommended intensity: level B).
2. For patients with vertebral osteoporotic fractures, it is recommended to strengthen core stability training and improve postural abnormalities (recommended intensity: level B).
3.For those individuals who are at risk of falling the most important exercise is tai chi, balance and gait training and other balance exercises (recommended intensity: level A).
4. For older adults who are at high risk for osteoporotic fractures and are receiving long-term care, hip protectors should be used (recommended intensity: level B).
▪ Calcium and vitamin D
1.The daily calcium requirement for people over 50 years old is about 1200mg (dietary intake + additional supplementation) (recommended intensity: level B).
2.For healthy adults with a low low risk of vitamin D loss, a daily supplementation of about 400-1000 IU of vitamin D is recommended, about 10-25 μg (recommended intensity: level D).
3. For people over 50 years of age who are at moderate risk of vitamin D loss, daily supplementation of about 800-1000 IU, about 20-25 μg of vitamin D. To achieve optimal vitamin D levels, daily supplementation should not be less than 1000 IU (25 μg). Even a daily vitamin D supplementation of 2000 IU (50μg) is safe and monitoring is not necessary (recommended strength: level C).
4. For patients receiving pharmacological treatment for osteoporosis, serological 25-OH vitamin D should be monitored approximately 3-4 weeks after adequate vitamin D supplementation. If the test value is normal (≥75 nmol/L), further monitoring is not necessary (recommended intensity: level D).
▪ Drug therapy
A growing number of medications have gained efficacy in Canada for osteoporosis, ranging from antiresorptive agents (bisphosphonates, receptor activators of core factor-κB ligand inhibitors, selective estrogen receptor modulators, hormone therapy, calcitonin, etc.) to pro-osteogenic agents (teriparatide), each with widely varying routes of administration, doses, and frequencies.
However, there is evidence from relevant randomized clinical trials that all these drugs reduce the risk of vertebral fractures in menopausal women with osteoporosis (T value ≤ -2.5). There is also evidence of effectiveness for non-vertebral fractures, such as hip fractures, and a significant reduction in mortality in those at high risk for fracture. The therapeutic effect is also clear in women with previous vertebral or hip osteoporotic fractures.
In general, pharmacological treatment reduces the risk of vertebral fracture by 30-70%, with the difference being related to the patient’s compliance with the treatment regimen. The treatment effect varies according to the fracture site and is relatively poor in non-vertebral fractures. Both calcitonin and teriparatide reduce pain associated with vertebral fractures.
Few studies have been conducted on the reduction of fracture incidence in men. Systematic review studies and Meta-analyses have found that vertebral fracture patients tend to have a significant reduction in diphosphonates, but testosterone has not been shown to reduce the incidence of fractures. Moreover, the fact that hypogonadal men respond similarly to bisphosphonate therapy
For menopausal women requiring osteoporosis treatment, alendronate, risedronate, zoledronic acid, and denosumab can be used as first-line agents to prevent osteoporotic fractures of the hip and vertebral and nonvertebral osteoporotic fractures (strength of recommendation: Class A).
2.For menopausal women who need anti-osteoporosis treatment, raloxifene can be used as the first-line drug for the prevention of vertebral osteoporotic fractures (recommended strength: Grade A).
3. For menopausal women requiring anti-osteoporosis therapy in combination with vasodilatory therapy, hormonal therapy can be used as a first-line drug for the prevention of osteoporotic fractures of the hip and vertebral and non-vertebral osteoporotic fractures (strength of recommendation: level A).
4. For menopausal women whose use of first-line therapeutic agents is contraindicated, calcitonin and etidronate disodium can be used as drugs for the prevention of vertebral osteoporotic fractures (recommended intensity: level B).
5.For men who need anti-osteoporosis treatment, alendronate, risedronate and zoledronic acid can be used as first-line drugs for the prevention of osteoporotic fractures (strength of recommendation: level D).
6. Testosterone is not recommended as an anti-osteoporosis treatment drug (strength of recommendation: level B).
Adverse effects
In this part we focus on common problems, or problems found in the post-marketing surveillance of drugs. Many of these problems, as yet, have not been addressed.
High dose calcium intake can lead to increased incidence of kidney stones as well as cardiovascular disease. Diphosphonates can lead to self-limiting flu-like symptoms, particularly prevalent with the first use of zoledronic acid, with a reported incidence of about 10%. Denosumab can lead to an increased incidence of cellulitis. Raloxifene and hormone therapy can lead to vascular embolism and even pulmonary embolism. Teriparatide can lead to the development of hypercalcemia and hypercalcemia, but it is relatively mild and the symptoms tend to resolve spontaneously or after stopping calcium supplementation.
There is still much controversy as to whether bisphosphonates for osteoporosis can cause osteonecrosis of the palate, atypical femoral fractures, esophageal cancer, or atrial fibrillation. Palatal osteonecrosis is the exposure of the palatal bone at the maxilla and mandible, which does not heal for 8 weeks, which is of course very rare, less than one case in 10,000patient-years of patients with primary osteoporosis.
Patients at relatively high risk are those with malignancies, those undergoing radiotherapy and chemotherapy, those receiving high doses of bisphosphonates and glucocorticoids, and those with a history of diabetes or poor oral hygiene, or those who have undergone minimally invasive oral surgery such as tooth extraction or implants.
Atypical fractures are those that occur in the intertrochanteric space or in the femoral stem. Although this symptom is significantly higher in patients treated with bisphosphonates, the correlation between these fractures has not been conclusively established. These fractures tend to present as transverse or oblique “pencil” fractures. X-rays may reveal cortical thickening of the fractured segment. Bone scans may reveal increased local nuclear uptake, suggesting a stress fracture with increased remodeling. X-rays or (and) bone scans should be performed in patients on long-term bisphosphonate therapy or in patients presenting with groin pain.
The U.S. Food and Drug Administration reported that from October 1995 to May 2008, a total of 23 cases of esophageal cancer were reported in patients treated with bisphosphonates, but no statistics were reported on esophageal cancer in patients not treated with bisphosphonates during the same period, and no valid controls were available. There is also a statistical finding of no significant difference in the incidence of esophageal cancer between patients treated with and without bisphosphonates. Two recent large retrospective cohort studies have come to the exact opposite conclusion.
Overall, for patients at high risk of osteoporotic fracture over the next 10 years, the benefits of drug therapy far outweigh the potential risks it poses.
1. The pros and cons of pharmacotherapy should be adequately discussed prior to treatment in order to develop an appropriate treatment plan (Grade of recommendation: D).
[Special groups].
Patients receiving glucocorticoid therapy can experience bone loss after about 3 to 6 months, and at about 2.5-7.5 mg/day, it can lead to a significantly increased risk of osteoporotic fracture. Long-term glucocorticoid use (more than 3 months) can lead to an incidence of osteoporotic fractures of approximately 30-50%, especially in those older than 40 years and in those using higher doses.
Osteoporosis treatments, including alendronate, risedronate and teriparatide all reduce the risk of vertebral osteoporotic fractures and maintain bone density in glucocorticoid users. Similarly, etidronate, zoledronic acid, and calcitonin have been shown to maintain bone mineral density in glucocorticoid users. The duration of treatment of osteoporosis in patients receiving long-term glucocorticoid therapy is inconclusive. Both bisphosphonates and denosumab maintain BMD in female patients treated with aromatase inhibitors and in male patients receiving androgen deprivation.
1, For people over 50 years of age receiving long-term glucocorticoid therapy (prednisolone dose ≥ 7.5 mg daily for more than 3 months), bisphosphonates (alendronate, risedronate and zoledronic acid) should be applied early and maintained continuously for at least the entire duration of glucocorticoid therapy (strength of recommendation: Grade A).
2. Teriparatide is recommended for people at high risk of fracture who are treated with glucocorticoids (prednisolone at a daily dose ≥7.5 mg for more than 3 months) (strength of recommendation: level A).
3.For people who are on long-term glucocorticoid therapy and contraindicated to use anti-osteoporosis first-line drugs, calcitonin and denosumab are recommended (recommended strength: level B).
4. Female patients treated with aromatase inhibitors and male patients treated with androgen deprivation therapy should be evaluated for osteoporotic fracture risk and given appropriate anti-osteoporosis treatment to prevent fractures (strength of recommendation: level B).
How to manage patients with osteoporotic fracture risk?
Comprehensive management of patients with osteoporotic fracture risk is very important. All patients should have appropriate weight training, balance and strengthening exercises, and are advised to quit smoking and to pay attention to the overall optimization of calcium and vitamin D in the body (normal diet and additional supplementation). For patients at risk of falls, fall prevention strategies should be implemented.
In a comprehensive treatment strategy, low, medium and high fracture risk groupings can be used to guide treatment. The ratio of pros to cons of treatment should be fully considered in clinical practice, especially for those who are not at high risk of fracture. A thorough assessment of the individual’s risk, other comorbidities, personal preferences and their lifestyle should be performed before choosing a specific treatment.
1. Anti-osteoporotic drug treatment regimens should be based on an assessment of the absolute risk of osteoporotic fracture, usually through a certain assessment system (recommendation level: D).
■ High risk
1. Patients in the absolute high-risk group (>20% risk of osteoporotic fracture in the next 10 years) are recommended to be given pharmacological treatment (recommendation grade: D).
2. Patients over 50 years of age with previous osteoporotic fractures of the hip and vertebrae, and patients with multiple previous osteoporotic fractures are in the high-risk group for future fractures and are recommended for pharmacological treatment (recommendation grade: B).
▪ Moderate risk
Many patients at intermediate risk of osteoporotic fracture should also be treated medically. More osteoporotic fractures occur in the intermediate risk group than in the high risk group, which is of course related to the higher number of patients in the intermediate risk group. Therefore, patients in the intermediate risk group should be carefully evaluated and risk factors outside the risk assessment system should be identified for appropriate pharmacological treatment.
1. For patients in the intermediate risk group, the patient’s personal preferences as well as additional risk factors will be used to guide treatment (recommendation level: C).
▪ Low-risk group
Patients in the low-risk group generally do not require pharmacotherapy. As long as there are no risk factors for rapid bone loss in the low-risk group, only appropriate lifestyle modifications such as increased exercise, fall prevention, optimal calcium and vitamin D intake, and smoking cessation are generally required.
Monitoring of treatment effects
Continuous monitoring of BMD after treatment is of great importance for the evaluation of clinical treatment effects, but there is a lack of relevant randomized trial studies. When statistical analysis of continuous measurements of BMD is performed, the measurement error should also be adequately taken into account to determine that the changes are valuable and meaningful, rather than random fluctuations or just individual chance phenomena. For patients receiving anti-osteoporosis treatment, continuous, repeated monitoring of BMD is important for 1-3 years after treatment, and once the effect of treatment has been determined, then the interval of monitoring can be extended appropriately.
If the patient’s bone mineral density increases or remains unchanged, then the treatment is considered to be effective. If there is a persistent decrease in BMD or a new osteoporotic fracture, the patient may be less compliant or less effective, or there may be other causes of the patient’s osteoporosis.
For patients in the intermediate risk group, including those with a T value of -2.5 or less, BMD should be measured repeatedly 1-3 years after treatment to monitor bone loss. If BMD levels are stable, then the frequency of monitoring can be reduced appropriately. For individuals in the low fracture risk group, and for individuals without the presence of additional risk factors contributing to bone loss, monitoring every 5-10 years is sufficient.
Under what circumstances should combination therapy be used or discontinued?
The time frame for treatment is not yet clear. A complete treatment cycle is 10 years, and one study found a 55% reduction in the incidence of osteoporotic fractures in patients who received complete treatment relative to those who stopped after five years of treatment, but no significant difference was found between vertebral fractures and non-cone type fractures. Discontinuation of bisphosphonate therapy or estrogen therapy can lead to a decrease in BMD. Estrogen combination therapy or the combination of raloxifene and a bisphosphonate can significantly increase BMD, but it is unclear whether this further reduces the incidence of fracture.
1, For patients at high risk of fracture, long-term drug therapy should be adhered to (Grade D).
2, Clinical attention should be paid to combination therapy to reduce fracture occurrence, not just the use of a single antiresorptive agent (Grade D).
Under what circumstances should patients seek help from a specialist?
Patients with the following conditions should consult a specialist in the field of osteoporosis: osteoporotic fracture or persistent decrease in bone mineral density despite adherence to first-line anti-osteoporosis therapy; contraindications to first- and second-line therapy; secondary causes of osteoporosis beyond the scope of the primary care physician’s guidance; severe low bone mineral density.
[Other Guidelines Introduction
The US National Osteoporosis Foundation (US-NOF) and the UK National Osteoporosis Guidelines Group (UK-NOGG) use a 10-year fracture risk assessment to guide treatment.US-NOF recommends that for menopausal women and men over 50 years of age with a hip or spine T value ≤ -2.5 or a history of previous hip fracture or spine fracture, both should be proactively intervened.
In addition, patients with low bone mass (T values between -1.0 and -2.5) should also be treated aggressively if they have a 10-year risk of hip fracture ≥ 3% or a 10-year risk of osteoporotic fracture ≥ 20%. 7.5% to 30% risk of osteoporotic fracture at age 80 years.
These two views conflict: the US-NOF guidelines are based on cost-effectiveness, whereas the UK-NOGG identifies treatment indications with a linear approach. Fewer patients are recommended to require treatment under the UK-NOGG principles than under US-NOF. It is unclear which is better or worse, or which is more appropriate for the Canadian population.
Knowledge Transfer]
The development of knowledge translation between these two guidelines was guided by the “knowledge-action” principle. A systematic review found that an osteoporosis management system for physicians and patients should be a comprehensive and integrated approach to improving BMD testing and guiding treatment, and should include a range of measures such as early warning, education, and risk assessment in paper or electronic format.
Several randomized controlled trials in Canada have confirmed the superiority of a comprehensive osteoporosis management system, in terms of effectiveness and cost-effectiveness. As a result, a toolkit and communication strategy was developed in consultation with primary care physicians, patients, specialists, relevant experts, imaging specialists and health policy makers. We brought together many Canadian experts and academics in osteoporosis and knowledge translation to develop the system and implement its implementation. More than 10 professional organizations have also reviewed and supported the promotion of this guideline.
1. Early education for patients as well as primary care physicians should be actively pursued after the occurrence of an osteoporotic fracture (recommendation level: B).
2. Holistic case management after osteoporotic fracture is a very effective method to improve the diagnosis and treatment of osteoporosis (recommendation level: A).
3. Individualization and other related management strategies are conducive to the implementation of osteoporosis guidelines in clinical practice (Recommendation grade: B).
[Future research directions].
There are still many gaps in how we prevent osteoporotic fractures and their adverse consequences. Future research should focus on the following directions: assessment of osteoporotic fracture risk in specific populations (including young patients with a history of previous osteoporotic fractures and young patients with a history of glucocorticoid use), the role of bone turnover factors in assessing individual osteoporotic fracture risk and monitoring treatment outcomes, whether exercise and fall prevention training are effective in reducing the incidence of fractures, and the optimal daily dose of vitamin D intake.