Updated Recommendations for the Diagnosis and Management of Osteoporosis: A Local Perspective

 [bib_ref] Hip fractures in the elderly: A worldwide projection, Cooper [/bib_ref] 

## What is new in this report?
- A review of local data, especially in relation to population specific BMD values and the correlation of BMD and risk factors to fracture risk. - An emphasis on the role of vitamin D deficiency and the need for correction. - A re-emphasis on the role of clinical risk factors in choosing patients for treatment. - A review of new international guidelines.
- A review of newer therapies.
- Pre-menopausal, adolescence and post-transplant osteoporosis in addition to osteoporosis in chronic renal failure patients, are addressed.

## Definition
Osteoporosis is a progressive, systemic skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.A fragility fracture is one that occurs as a result of either an injury that is insufficient to fracture normal bone, or no identifiable trauma. [bib_ref] Scientific advisory council of the osteoporosis society of Canada. 2002 clinical practice..., Brown [/bib_ref] Postmenopausal osteoporosis is a function of bone mass achieved at maturity and subsequent bone loss that is accentuated in the early postmenopausal period, and is influenced by certain risk factors. Previously emphasis was on the mineral content and bone mass (as measured by BMD), whereas the current understanding of osteoporosis puts an equal importance on bone quality and the architecture of the bone that includes, among others, the intrinsic properties of the bone represented by the collagen content and mineralization, and the micro-and macro-architecture of the bone represented by the porosity of cortical bone and the thickness and connectivity of trabeculae. [bib_ref] Bone architechture: Collagen structure and calcium/phosphorus maps, Tzaphlidou [/bib_ref] Other mechanical factors may also play a role in the tendency of a long bone to fracture. [bib_ref] Improving risk assessment: Hip geometry, bone mineral distri bution and bone strength..., Crabtree [/bib_ref] At this time, however, BMD remains the best available clinical tool in determining bone strength.

## The burden of osteoporosis in the region
Today, osteoporosis is a major public health problem that has both a medical and economic impact especially in developed countries. Fractures caused by either osteoporosis or low bone mass can lead to chronic pain, disability and even death, as well as psychological symptoms, including depression. [bib_ref] Association of severe vertebral fractures with reduced quality of life, Crans [/bib_ref] Each year broken bones due to low bone mass or osteoporosis cause over 432 000 hospital admissions, almost 2.5 million medical office visits, and about 180 000 nursing home admissions in the USA. [bib_ref] Estimating hip fracture morbidity, mortality, and costs, Braithwaite [/bib_ref] The osteoporosis problem will soon be of greater importance in developing countries since there is an increase in life expectancy. According to WHO estimates, hip fractures will increase from about 600 000 in 1990 to over 3 million in Asia by year 2020. 2

## Regional bone mineral density data
Osteopenia and osteoporosis are more common in our local population than in Western countries. In a study of 483 postmenopausal Saudi women 52-62 years of age, Al Desouki found the rate of osteopenia and osteoporosis to be 34% and 24%, respectively. [bib_ref] Osteoporosis in postmenopausal Saudi women using dual X-ray bone densitometry, El-Desouki [/bib_ref] In a study by Al Ghannam et al of 321 healthy Saudi women, the prevalence of osteoporosis was 1.0%, 5.6%, and 28% for age groups 31-40 years, 41-50 years, and >50 years, respectively. [bib_ref] Bone mineral density of the spine and femur in healthy Saudi females:..., Ghannam [/bib_ref] In the same study, the prevalence of osteopenia in the respective age groups was 18%, 18.4%, and 38% [fig_ref] Figure 1: Prevalence of osteopenia and osteoporosis in a study of 321 healthy Saudi... [/fig_ref]. Severe vitamin D deficiency was present in 52% of the subjects. BMD in healthy Saudi females was significantly lower than in their counterparts in the United States.
In an effort to create a local BMD reference range, studies were undertaken in different regional countries and mainly in female populations. Most studies found lower BMD than the standard established for the US/European reference data, except the Kuwait study, where the BMD reference range was similar. [bib_ref] Bone density measured by dual-energy X absorptiometry in healthy Kuwaity women, Dougherty [/bib_ref] In Saudi Arabia, Ardawi et al studied a group of 1980 Saudi males and females aged 20 to 79 years. The prevalence of osteoporosis in women was 44.5% using the manufacturer's reference values compared to only 28.2% when the Saudi reference values were used. On the other hand, more Saudi men were diagnosed with osteoporosis when local reference values were used [fig_ref] Table 1: Prevalence of osteopenia and osteoporosis in Saudi population [/fig_ref].These studies suggest that the age-related reference data are different in local populations from that used previously by manufacturers of bone densitometers. We therefore recommend the use of the Saudi reference range in BMD studies of Saudi patients in Saudi Arabia.

## Local fracture data
Local and regional information about osteoporosis and fracture rates is sparse. In a study from Lebanon, Baddourah et al found the lifetime risk for all fractures to be 9.3% in males, and 16.7% in females. [bib_ref] Incidence of fractures after the age of 50 years in the Lebanese..., Baddoura [/bib_ref] This rate is higher than other Asian countries, but less than Europe. Based on a study of Saudi patients >40 years of age who were admitted to local acute care hospitals in Riyadh with proximal femur fractures, Al-Nuaim et al estimated the incidence of proximal femur fractures per 100 000 population as shown in [fig_ref] Table 2: Proximal femur annual fracture rates per 100 000 population in Saudi subjects... [/fig_ref]. [bib_ref] Incidence of proximal femur fracture in an urbanized community in Saudi Arabia, Al-Nuaim [/bib_ref] These data indicate lower fracture rates than what has been reported from the West. This might be related to genetic factors that may influence bone quality, or more likely cultural and lifestyle differences. Unfortunately, there is no real fracture registry in most regional countries.

## The role of vitamin d deficiency
An acceptable international definition of vitamin D deficiency is a value below 50 nmol/L (20 ng/mL). Vitamin D insufficiency is defined as a value of 50-70 nmol/L and a desirable level is above 70 nmol/L. Local studies are needed to verify these values. Hypovitaminosis D is highly prevalent in the regional countries. Several studies showed widespread vitamin D deficiency. In one study from Lebanon, [bib_ref] Hypovitaminosis D in a Sunny country: Relation to lifestyle and bone markers, Gannage-Yared [/bib_ref] 72.8% of the population was affected by vitamin D insufficiency (defined by a 25(OH)D value below 15 ng/mL or 37 nmol/L), with women being at higher risk than men (83.9% vs. 48.5%). Moreover, inadequate vitamin D intake, urban dwelling, veil wearing and high parity were predictors of low vitamin D in the same study. Another study in schoolchildren 10 to 16 years old showed that 52% of the children were vitamin D insufficient (below 20 ng/mL or 50 nmol/L). The proportion of vitamin D insufficiency was 65% in the winter and 40% at the end of the summer. Girls, especially those with a lower (socio-economic status) were at particular risk.Studies from Saudi Arabia confirmed the widespread vitamin D deficiency among different groups of the population. Fonesca et al found a normal range of vitamin D levels only in 3 of 31 relatively health Saudi women with median level of 6 ng/mL or 15 nmol/L. In this study the low level of vitamin D correlated with urban dwelling and low sun exposure.
In 100 Saudi mothers and their newborns, Taha et al found that 59 mothers and 70 newborns had levels below 10 ng/mL or 25 nmol/L. [bib_ref] Exposure to sunlight and vitamin D deficiency in Saudi Arabian women, Fonseca [/bib_ref] [bib_ref] 25-Hydroxyvitamin D and total calcium: Extraordinarily low plasma concentrations in Saudi mothers..., Taha [/bib_ref] These and other studies emphasize the need for urgent measures such as vitamin D supplementation in some food items like milk. The major causes of vitamin D deficiency in the local population are most probably low intake and inadequate supplements in addition to low sun exposure. [bib_ref] Low calcium and vitamin D intake in healthy children and adolescents and..., Salamoun [/bib_ref] [bib_ref] Dietary calcium and vitamin D intake in an adult Middle Eastern population:..., Gannage-Yared [/bib_ref] Another possible contributing cause may be related to accelerated metabolism of vitamin D seen in certain ethnic groups. [bib_ref] Vitamin D metabolism is altered in Asians Indians in the southern United..., Awumey [/bib_ref] The effect of vitamin D on bone health has been well established. Bone density in a large population of postmenopausal women with osteoporosis correlated inversely with vitamin D levels. [bib_ref] A global study of vitamin D status and parathyroid function in postmenopausal..., Lips [/bib_ref] It has also been shown that lower vitamin D levels may contribute to the frequently encountered, severe bone manifestations, seen with primary hyperparathyroidism in Saudi Arabia and other countries with widespread vitamin D deficiency. [bib_ref] The effect of vitamin D status on the severity of bone disease..., Raef [/bib_ref] Vitamin D deficiency should therefore be suspected and adequately treated in all patients with osteopenia and osteoporosis in our region. In severe cases of vitamin D deficiency, large loading doses of a few hundred thousand units of cholecalciferol or ergocalciferol are usually given by IM route (200 000-300 000 units IM bolus) or preferably by oral route at intervals (50 000 weekly for a few weeks). Maintenance doses higher than the usually recommended dose of 400 units daily may be needed (800-1000 units daily). Malabsorption such as in celiac disease can be found even without frank GI symptoms and should be suspected and ruled out in unexplained severe cases.

## Evaluation/diagnosis
Optimal evaluation consists of establishing the diagnosis of osteoporosis on the basis of bone mass assessment, establishing the fracture risk, and determining the need for therapy. Bone strength is related to the density and quality of bone. There is at present no accurate measure for bone quality. BMD is considered a surrogate measure of bone strength. Dual-energy X-ray absorptiometry (DXA) is the preferred technique to measure BMD, and is the technique used at most centers. Quantitative ultrasound is useful for screening for osteoporosis.
The hip is the preferred site for BMD measurement due to the high predictive value of hip BMD for fracture risk, particularly in the elderly. [bib_ref] Screening for postmenopausal osteoporosis: A review of the evidence for the US...., Nelson [/bib_ref] BMD measurement at the spine predicts spine fracture better than measurements at other sites. However, spine changes may affect BMD measurement. The World Health Organization (WHO) has established the following operational definition for osteoporosis based on BMD as measured by DXA, commonly expressed as a T-score [fig_ref] Table 3: World Health Organization definition of osteoporosis [/fig_ref].
A history and a physical examination to evaluate fracture risk should include assessment for loss of height and change in posture. Laboratory evaluation for secondary causes of osteoporosis should be considered when osteoporosis is diagnosed. Serum calcium, phosphorus, alkaline phosphatase, creatinine, vitamin D, complete blood count and thyroid stimulating hormone (TSH) levels are usually sufficient baseline tests.

## Definition criteria
Normal BMD within -1 SD of reference mean for young adults Low bone mass (osteopenia) BMD within -1.0 and -2.5 SD lower than reference mean for young adults Osteoporosis BMD less than -2.5 SD lower than reference mean for young adults Severe Osteoporosis as defined above with one or more fragility fractures BMD= bone mineral density, SD= standard deviation Further laboratory tests can be done as clinically appropriate, such as parathyroid hormone level, urine free cortisol, liver function tests, or serum immune electrophoresis. Biochemical indices of skeletal turnover could potentially be helpful in the diagnosis and monitoring of therapy. However, as their role has not been fully elucidated, they are not yet recommended in routine clinical management. The drop of bone resorption markers in response to antiresorptive therapy occurs before a significant change in BMD. This may explain the decrease in fracture rates seen early with such therapy, before changes in BMD. 27

## Using risk factors in selecting patients for diagnosis and therapy: the fracture risk assessment tool
The osteoporosis working group has previously advocated the use of risk factors in selecting patients for diagnostic tests and for treatment of osteoporosis. In their previously published recommendations, a fracture index tool was suggested using a few important and easily assessed risk factors. [bib_ref] Recommendations for the diagnosis and management od osteoporosis: A local perspective, Raef [/bib_ref] [bib_ref] WHO publication -Kanis JA, on behalf of the World Health Organisation Scientific..., Black [/bib_ref] The argument made by the group was that a mere BMD assessment is likely to result in overtreatment in a local population, with evidence of lower BMD values but fewer fractures than in a Western population. The concept of using risk factors to determine those at higher fracture risk has recently been adopted by the WHO and many international societies. A group of international experts, under a project by the WHO, has developed a tool to assess the absolute risk for fracture based on known risk factors. These estimates were based on different ethnic groups and populations across the world. Absolute fracture risk methodology provides a markedly improved method to assure that people with the highest fracture risk get treated. In addition, absolute fracture risk calculations help to resolve many of the questions about management for people with low bone mass (osteopenia). With the Fracture Risk Assessment (FRAX) tool, these individuals and their clinicians have information from absolute fracture risk methodology to determine when it is medically appropriate to treat and when it is not necessary to treat based on the likelihood of fracture in such patient.
The 10 risk factors used in the FRAX are: For the FRAX estimate to work, a threshold for treatment based on the absolute risk has to be adopted in each population, country or region. [bib_ref] Cost-effective osteoporosis treatment thresholds: The United States perspective, Tosteson [/bib_ref] The threshold at which treatment is recommended would have to be decided based on the health economics of preventing fracture in each population. This in turn is decided by the fracture rates and the cost-effectiveness of treatment to prevent hip or other major fractures and the priorities of the health care in that population. For the US this was estimated to be a 10-year risk of 3% for hip fractures and 20% for other fractures. A risk higher than 3% for hip fracture based on the FRAX would justify treatment in an osteoporotic or even osteopenic subject in the US. [bib_ref] Cost-effective osteoporosis treatment thresholds: The United States perspective, Tosteson [/bib_ref] The pitfalls for the use of FRAX in our local population are:

## - 
The database for the FRAX does not include our region; such local databases are essentially lacking.

## - 
The tool was not verified in local studies. - Some of the risk factors included are not well defined such as the "ever use of steroids" - 
The risk for falling due to muscle weakness or visual impairment is not included as a risk factor, though was found to be quite important by other studies.

## Nevertheless, the use of risk factors in choosing high risk population for further diagnostic tests and management is extremely important for cost effective management in our region.

## Using risk factors in the local population
One important issue is whether generally used risk factors for osteoporosis or fractures are valid for a specific population. There are very few studies done in the region to address this question. One of these studies was performed in Turkey, to assess the risk variables for osteoporosis. The study was conducted on 126 postmenopausal healthy women as a control group and 225 postmenopausal osteoporotic women. The study suggested that low levels of dietary calcium intake, physical activity, education, and a longer duration of menopause are independent predictors of the risk of low bone density in that population. [bib_ref] Determination of osteoporosis risk factors using a multiple logistic regression model in..., Akkus [/bib_ref] In another study carried out in Qatar on healthy females age 20 to 70 years, risk factors for osteoporosis were not different from known factors in Western studies, such as female sex, age, early menopause and excessive smoking. However, the study suggested other locally important risk factors like a high number of pregnancies, prolonged lactation and vitamin D deficiency. 32

## The correlation of bmd to fractures and use of local versus international databases for bmd and risk factors
The only correlation study we are aware of for BMD versus fractures in the region was recently published. [bib_ref] Vertebral fracture risk and impact of database selection on identifying elderly Lebanese..., Baddoura [/bib_ref] The study aimed at estimating the prevalence of vertebral fractures in the Lebanese elderly, determining the BMD-fracture relationship, and assessing the effect of database selection on osteoporosis prevalence and fracture risk assessment. The prevalence of vertebral fractures was estimated at 19.9% in women and at 12.0% in men. The prevalence of osteoporosis by DXA using total hip was 33.0% in women and 22.7% in men. The NHANES database (The US National Health and Nutritional Examination Survey) provided a higher sensitivity for vertebral fracture than a local populationspecific database. The relative risk of vertebral fracture per one standard deviation decrease in BMD remained unchanged across the two databases. This would support the notion that the use of an international database of risk factors in predicting fractures in a local population may be valid. However, this is not verified in the Gulf region.

## Screening for osteoporosis in postmenopausal women and elderly men
Some international guidelines for osteoporosis screening recommend BMD testing for all women age 65 years or older, and for postmenopausal women under age 65 years (especially 60-64 years) who have one or more additional high-risk factors for osteoporosis. [bib_ref] Screening for postmenopausal osteoporosis: A review of the evidence for the US...., Nelson [/bib_ref] More liberal recommendations were made by other societies. However, as BMD is generally lower in Saudi women compared to their Western counterparts, they may develop osteoporosis and fractures at an earlier age. It is also relevant that physical activity and therefore the risk of falling may be less in local females older than 65 years due to different cultural habits. Thus, it is reasonable to start screening postmenopausal Saudi women at an earlier age than that recommended for Western women. We stress that BMD measurement should only be done if it will influence the management decision.
The KFSH task force has found that the recent

## Major recommendation to clinicians (from the nof 2008 clinician's guide)
For postmenopausal women and men age 50 and older:
- Counsel on the risk of osteoporosis and related fractures. - Check for secondary causes.
- Advise on adequate amounts of calcium (at least 1200 mg/d, including supplements if necessary) and vitamin D (800 to 1000 IU per day of vitamin D3 for individuals at risk of insufficiency). - Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures. - Advise avoidance of tobacco smoking and excessive alcohol intake. - In women age 65 and older and men age [bib_ref] Adolescents: At increased risk for osteoporosis?, Cromer [/bib_ref] and older recommend BMD testing. - In postmenopausal women and men age 50-70, recommend BMD testing when you have concern based on their risk factor profile. - Recommend BMD testing to those who have suffered a fracture, to determine degree of disease severity. - Initiate treatment in those with hip or vertebral (clinical or morphometric) fractures. - Initiate therapy in those with BMD T-scores <-2.5 at the femoral neck, total hip, or spine by DXA, after appropriate evaluation. - Initiate treatment in postmenopausal women and in men age 50 and older with low bone mass (T-score -1 to -2.5, osteopenia) at the femoral neck, total hip, or spine and 10-year hip fracture probability =3% or a 10-yr all major osteoporosis-related fracture probability of =20% based on the US-adapted WHO absolute fracture risk model. - BMD testing performed in DXA centers using accepted quality assurance measures is appropriate for monitoring bone loss (recommendation every 2 years). For patients on pharmacotherapy, it is typically performed two years after initiating therapy and at 2-year intervals thereafter.
National Osteoporosis Foundation (NOF) revised guidelines for screening to be useful. These guidelines recommend screening for the following subjects:
- Women 65 and older and men [bib_ref] Adolescents: At increased risk for osteoporosis?, Cromer [/bib_ref] DEXA remains the gold standard for measurement of BMD, especially as a diagnostic tool. Other tools like ultrasound of the calcaneal bone can be used for general screening. DEXA is also the only tool for which the WHO definition of osteoporosis applies.

## Clinical manifestations and complications
Osteoporosis is a silent disease, as bone loss occurs without symptoms. Most of the time there are no warning signs until a fragility fracture occurs. Osteoporosisrelated fractures may occur in any bone, but are most likely to occur at sites of low bone mass. The most typical sites of osteoporosis-related fractures are the vertebrae, distal radius, proximal femur, and ribs. The morbidity of osteoporosis comes mainly from fractures and their potential complications. Vertebral compression fractures are associated with pain, deformity, disability, and increased mortality. [bib_ref] Association of severe vertebral fractures with reduced quality of life, Crans [/bib_ref] The most serious consequences, however, are those associated with hip fractures. In one study on elderly subjects who sustained hip fractures, the life expectancy was reduced by 1.8 years or 25% compared to a matched population. There was also a significant increase in morbidity and health costs in those who had hip fracture. 10

## Prevention of osteoporosis
Prevention is the most important measure in addressing low BMDs in the youth and in women during reproductive age. Frequent pregnancies and lactation may predispose women in our society to lower BMDs. Thus, proper nutritional and family planning advices are warranted for this group. Another important group to target for prevention is postmenopausal women, and those with conditions predisposing to osteoporosis like amenorrhea.
Initiatives should be directed at the following measures:
- 
Optimal nutrition in the youth to achieve high peak bone mass, including adequate intake of calcium and vitamin D.

## Osteopenia and fractures
Although patients with lower BMD are at high risk of fractures, studies have shown that the largest number of osteoporotic fractures occurred among those with osteopenia (BMD -1 to -2.5). [bib_ref] Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal..., Siris [/bib_ref] [bib_ref] Indentification of Osteopenic Women at high risk of fracture: The OFELY study, Sornay-Rendu [/bib_ref] This can be explained by the presence of larger number of subjects with osteopenia than with osteoporosis and therefore even with a lower risk for fractures, the number of fractures can be substantial. Also it may reflect the influence of other risk factors. On the other hand, the value of antiresorptive agents for fracture prevention has not in general been proven in osteopenic subjects with no prior fractures, although such treatment might improve or stabilize BMD. Therefore, the use of pharmacological agents like antiresorptives in osteopenic subjects, should be limited to those with history of fractures or to those with multiple risk factors for fractures.

## Specific types of osteoporosis

## Premenopausal osteoporosis
The present evidence does not support screening for osteoporosis in premenopausal women in the general population. Certain premenopausal and perimenopausal women, however, are at a higher risk of accelerated bone loss, but there is no clear strategy to identify those individuals. There is some evidence to support screening premenopausal or peri-menopausal women who have one of the following:
- Fragility fracture - Frequent or prolonged use of corticosteroids 5 mg of prednisone for 3 months or longer - Prolonged or recurrent amenorrhea
[formula] - Primary hyperparathyroidism - Rheumatoid arthritis - Prolonged hyperthyroidism [/formula]
It is important to realize that premenopausal women who have low BMD have a lower risk for fracture than older subjects with the same BMD. Osteoporosis cannot therefore be diagnosed simply based on low BMD in a premenopausal woman. Many premenopausal women with low BMD had simply not achieved an adequate peak bone mass at a younger age. Common causes of low BMD in this category are low body weight and ovulatory disturbances. Secondary causes have always to be ruled out when osteoporosis is discovered. Workup may include ruling out calcium and metabolic bone diseases including vitamin D deficiency, liver or renal diseases, celiac disease and malabsorption, hypogonadism and other secondary causes of osteoporosis. The use of antiresorptive therapy can be recommended only in very specific cases like those with low BMD and prolonged corticosteroid therapy and in certain cases of primary hyperparathyroidism when surgery is not feasible and treatment is indicated. [bib_ref] Premenopausal women and low bone density, Khan [/bib_ref] [bib_ref] Bone densitometry in premenopausal women, Khan [/bib_ref] Steroid-Induced osteoporosis The American College of Rheumatology recommends the following interventions for prevention of bone loss and fractures in high-risk patients (postmenopausal women, elderly men) or younger patients with a BMD T-score (spine or hip) of less than -1 who are initiating prednisone at a dose of 5 mg/day or higher (or equivalent dose of a glucocorticoid) for more than three months: 40 The patient should be followed yearly to determine if bone loss continues. An exercise program should also be initiated, although this may be limited by restrictions from the underlying illness. Other published guidelines largely agree with the recommendations above, except for some minor differences. [bib_ref] A UK Consensus Group on management of glucocorticoid-induced osteoporosis: An update, Eastell [/bib_ref] A recent study indicated that teriparatide (parathyroid hormone analogue) may increase BMD more effectively when compared to alendronate in the prevention of steroid-induced osteoporosis. [bib_ref] Teriparatide or Alendronate in glucocorticoid-induce osteopo rosis, Saag [/bib_ref] Zoledronic acid was also recently approved for prevention of steroid induced osteoporosis. [bib_ref] for the HORIZON investigators Zoledronic acid and risedronate in the prevention and..., Reid [/bib_ref] In addition to the above recommendations, the task force made the following recommendations for the prevention of steroid-induced osteoporosis:
- 
In certain cases zoledronic acid may be considered if oral therapies were not possible and the duration of steroid intake is prolonged or indefinite.

## - 
Women with premature hypogonadism, should be considered for estrogen therapy.

## Osteoporosis in solid organ transplantation
Osteoporosis is found in up to half of transplant recipients, whereas incidence of fractures after transplantation ranges from 10% to 65%. [bib_ref] Osteoporosis after solid organ and bone marrow transplantation, Cohen [/bib_ref] [bib_ref] Osteoporosis after organ transplantation, Rodino [/bib_ref] The decrease in BMD occurs in the first 3 to 6 months and is probably related to the large doses of glucocorticoids used immediately after grafting. Early bone loss at the lumbar spine is typical of glucocorticoid-induced bone loss, followed few months later by femoral neck site bone loss that may exceed that at the lumbar spine, and most studies do not document recovery of bone mass at the hip. Reports on BMD changes after renal transplantation differ. The rapid and significant early loss in BMD in the first 6 months may be followed by continued loss of approximately 1% yearly, up to 8 years after renal transplantation. In heart and liver transplant recipients, the incidence of new fractures parallels the timing of the most rapid loss of BMD, with most fractures occurring within the first year after transplantation. After renal transplantation, the incidence of fracture remains elevated, consistent with the persistent decline in BMD. Many factors contribute to the pathogenesis of osteoporosis after organ transplantation. These include bone disease preceding transplantation, immunosuppressive medications, poor nutrition, immobility, hypogonadism, cachexia (lower body mass index), postmenopausal status and lifestyle factors (smoking and alcohol abuse). The mechanisms of glucocorticoid-induced osteoporosis are multiple. Early on, a phase of rapid bone loss is probably secondary to an increase in bone resorption due to a combination of renal calcium wasting, decreased intestinal absorption of calcium, and hypogonadotropic hypogonadism. In addition, glucocorticoids directly promote osteoclastogenesis (bone resorption). Bone formation is also profoundly inhibited. In addition glucocorticoids can induce a profound myopathy, impairing balance and mobility and increasing fall risk and the potential for fractures. [bib_ref] Osteoporosis after organ transplantation, Rodino [/bib_ref] [bib_ref] Medical complications of lung transplantation, Lyu [/bib_ref] Prevention and management of transplant-induced osteoporosis The literature regarding prevention and treatement of transplant-associated bone loss is plagued by relatively small numbers of patients with insufficient power to detect significant differences in BMD, differing immunosuppressant regimens, no randomization, or randomization at varying intervals following transplantation. Moreover, the vast majority of studies are not powered to detect fracture outcomes. [bib_ref] Management of bone loss after organ transplantation, Cohen [/bib_ref] Because rates of bone loss and fracture incidence are highest immediately after transplantation, preventive and therapeutic measures should be instituted at that time and without delay. In addition, the lack of reliable clinical predictors to identify individual patients who will experience osteoporotic fractures makes all transplant recipients candidates for preventive therapy regardless of their base line bone density. [bib_ref] Management of bone loss after organ transplantation, Cohen [/bib_ref] Specific resistance training and exercises were shown to help to restore BMD levels more rapidly with alendronate, than alendronate alone. [bib_ref] Osteoporosis after organ transplantation, Rodino [/bib_ref] Improving overall fitness is recommended to minimize the risk of falling before and following transplantation. [bib_ref] Management of bone loss after organ transplantation, Cohen [/bib_ref] Vitamin D and calcium should be given to all patients at recommended daily allowance for calcium (1000-1500 mg/d) and for vitamin D (400-800 IU/d) with 25-hydroxyvitamin D levels monitored to assess the adequacy of replacement. [bib_ref] Osteoporosis after organ transplantation, Rodino [/bib_ref] Vitamin D and calcium alone are clearly insufficient to prevent transplant-related bone loss or fractures. [bib_ref] Ef fect of calcitriol on bone loss after cardiac or lung transplantation, Sambrook [/bib_ref] [bib_ref] Wetzels JF. Treatment with vitamin D and cal cium reduces bone loss..., Sevaux [/bib_ref] There are no specific FDA-approved therapies for posttransplantation osteoporosis. Bisphosphonates are clearly the drugs of choice for steroid-induced osteoporosis and any patient who meets WHO criteria for osteoporosis should receive pharmacologic treatment. Also the recommendations stated above by the American College of Rheumatology for prevention of steroid-induced osteoporosis should be followed. Limited data suggest that pretransplant treatment with bisphosphonates decreases posttransplant fracture risk.
When administered prior to liver transplant, intravenous pamidronate prevented osteoporotic vertebral collapse. [bib_ref] Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: A..., Leidig-Bruckner [/bib_ref] Similarly, in a prospective, uncontrolled pilot study using intravenous pamidronate in lung transplant recipients, the fracture rate decreased and bone mass preserved at 1-year posttransplantation. [bib_ref] Preven tion of bone loss and fracture after lung trans plantation: A..., Cahill [/bib_ref] In a study of renal transplant recipients, repeated doses of intravenous pamidronate preserved vertebral BMD during treatment and 6 months after cessation of treatment. [bib_ref] Pre vention of bone loss in renal transplant recipients: A prospective, randomized..., Coco [/bib_ref] In renal transplant recipients, alendronate started immediately after grafting reduced bone loss in a nonrandomized study. [bib_ref] Prevention of bone loss in kidney graft recipients, Kovac [/bib_ref] Trials using zoledronic acid has also given positive results. [bib_ref] Zoledronic acid to prevent bone loss in the first 6 months after..., Haas [/bib_ref] Calcitonin seems to be ineffective in preventing early bone loss, but may have some benefit in the later post-transplant period in liver [bib_ref] Calci tonin and bisphosphonates treatment in bone loss after liver transplantation, Valero [/bib_ref] and renal 57 transplant recipients and can be considered a safe alternative if other agents are contraindicated or poorly tolerated.
Recombinant parathyroid hormone (teriparatide) has also been evaluated recently. [bib_ref] Effect of teriparatide onearly bone loss after kidney transplantation, Cejka [/bib_ref] Its usefulness may be limited because of the secondary hyperparathyroidism commonly observed in long-term transplant recipients. [bib_ref] Osteoporosis after organ transplantation, Rodino [/bib_ref] Gonadal hormone replacement may be beneficial in premenopausal women and men undergoing solid organ transplantation who may have temporary hypogonadism. [bib_ref] Serum testosterone levels after cardiac transplan tation, Fleischer [/bib_ref] Testosterone replacement, started 6 months after cardiac transplantation in hypogonadal men who were also receiving calcium and vitamin D, stabilized BMD at the lumbar spine within 24 months. [bib_ref] Osteoporosis after organ transplantation, Rodino [/bib_ref] In the renal transplant population, bisphosphonates are potentially nephrotoxic. Acute renal failure with acute tubular necrosis in association with several intravenous bisphosphonates has been reported. [bib_ref] Se vere osteoporosis before and after lung transplan tation, Aris [/bib_ref] [bib_ref] Bone mass in patients with type 1 diabetes mellitus awaiting simultaneous pancreas..., Desso [/bib_ref] There remain significant concerns for the use of bisphosphonates in renal patients with preexisting low bone turnover disease, wherein bisphosphonates could further slow bone turnover and potentially increase fracture rate. [bib_ref] Bisphosphonates and bone fractures in long-term kidney transplant recipients, Conley [/bib_ref] Studies of oral calcitriol in solid organ transplantation gave mixed results. Spinal bone loss was not prevented with low dose of calcitriol, 0.25 mcg/d or 0.5 mcg/48 h in heart and kidney recipients. [bib_ref] Wetzels JF. Treatment with vitamin D and cal cium reduces bone loss..., Sevaux [/bib_ref] In a randomized, double-blind study, calcitriol (0.5-0.75 g/d) reduced proximal femur bone loss in heart and lung transplant recipients despite no decrease of lumbar spine bone loss. [bib_ref] Ef fect of calcitriol on bone loss after cardiac or lung transplantation, Sambrook [/bib_ref] There are few data to guide duration of therapy in transplant recipients. Treatment duration should be based upon patient factors, such as ability to withdraw glucocorticoids, presence of other risk factors for low bone mass and fracture, and BMD measurements. In some patients, 12 months of therapy may be adequate. [bib_ref] Osteo porosis and lung transplantation: A prospective study, Spira [/bib_ref] [bib_ref] Discontinuing antiresorptive therapy one year af ter cardiac transplantation: Effect on bone..., Cohen [/bib_ref] In conclusion, there is a great need for strategic approaches to osteoporosis in transplantation at KFSHRC. Because bone disease is common, all transplant candidates should be evaluated and treated before transplantation to improve skeletal health. Preventive and therapeutic measures should be instituted at that time and without delay.

## Treatment of osteoporosis in adolescents
Throughout childhood and adolescence, the skeleton changes in both size and shape. Bones are growing in length and width, cortical thickness is increasing, and there is a dramatic increase in bone mass as well as a significant increase in bone density. All these processes are influenced by genetic, hormonal and environmental factors. [bib_ref] Osteoporosis in children and adolescents, Bianchi [/bib_ref] Conditions that result in pubertal retardation in adolescents of both sexes, such as chronic diseases, hypogonadism or anorexia nervosa can lead to osteoporosis. In recent years, the issue of low bone mass/low bone density in children and adolescents has attracted much attention. The interpretation of data in the young is difficult because the "normal" BMD values to be used for comparison are continuously changing with age, and depend on several variables, such as gender, body size, pubertal stage, skeletal maturation and ethnicity. For children these values must be adjusted for age and sex (Z-score). [bib_ref] Osteoporosis in children and adolescents, Bianchi [/bib_ref] Z-score values below -2 are generally a serious warning, most bone specialists make a diagnosis of osteoporosis in children and adolescents only in the presence of low BMD and at least one fragility fracture. [bib_ref] The spectrum of pediatric osteoporosis, Ward [/bib_ref] This is more easily accepted in children affected by a chronic disease that is known to cause secondary osteoporosis, but the problem is present, and is even more complex, in adolescents who are apparently healthy, but have a low bone density.
There is still no consensus on the treatment of osteoporosis in the young with the exception of osteogenesis imperfecta. The lack of randomized trials comparing drugs and doses in various conditions makes it is impossible to declare one therapeutic regimen superior to another. [bib_ref] The spectrum of pediatric osteoporosis, Ward [/bib_ref] [bib_ref] How to manage osteoporosis in children, Bianchi [/bib_ref] [bib_ref] Clinical review 1: Bisphosphonate use in childhood osteoporosis, Bachrach [/bib_ref] Effective control of the under-lying disease is the best first-line approach to prevent secondary osteoporosis. Growth retardation, pubertal delay, or hypogonadism must be corrected with appropriate hormonal therapy. The identification of osteoporosis risk factors is very important.
Treatment of osteoporosis in adolescents includes adequate calcium dietary intake and correction of vitamin D deficiency which is a common problem among otherwise healthy young patients. A vitamin D level above 50 nmol/L (20 ng/mL) in children is considered optimal. [bib_ref] How to manage osteoporosis in children, Bianchi [/bib_ref] Physical activity (high-intensity impact activities, such as running, jumping, or basketball for 10 to 20 minutes, at least 3 days per week) proved to be helpful. [bib_ref] Adolescents: At increased risk for osteoporosis?, Cromer [/bib_ref] Regarding antiresorptive drugs, only bisphosphonates have been successfully used in children. They are regularly used in children with severe osteogenesis imperfecta or osteoporosis related to cerebral palsy, in which the repeated fractures dramatically affect the quality and expectancy of life. [bib_ref] Osteogenesis imperfecta: A clinical study of the first 10 years of life, Vetter [/bib_ref] Bisphosphonate treatment in children and adolescents is not currently approved by the FDA. [bib_ref] Osteoporosis in children and adolescent girls: Case report of idiopathic juvenile osteoporosis..., Kauffman [/bib_ref] Bisphosphonates have been shown to increase BMD, relieve pain, increase mobility, and reduce fragility fractures in osteogenesis imperfecta, corticosteroid-induced osteoporosis and other secondary osteoporosis (in connective tissue diseases, renal insufficiency, cerebral palsy). Intravenous cyclical pamidronate or oral alendronate have been used most often. [bib_ref] Efficacy and safety of alendronate for the treatment of osteo porosis in..., Bianchi [/bib_ref] [bib_ref] Bisphosphonate treatment of bone disease, Shaw [/bib_ref] Use of bisphosphonate therapy in pediatric patients remains controversial because of inadequate long-term efficacy and safety data. For this reason, many experts recommend limiting use of these agents to those children with recurrent extremity fractures, symptomatic vertebral collapse, and reduced bone mass. Current data are inadequate to support the use of bisphosphonates in children to treat reductions in bone mass/density alone. [bib_ref] Clinical review 1: Bisphosphonate use in childhood osteoporosis, Bachrach [/bib_ref] The anabolic agent teraparatide has also been used in some cases to promote bone formation.

## Treatment of osteoporosis in chronic renal failure and endstage renal disease
The diagnosis of osteoporosis in chronic renal failure is not easy to make due to the confounding effects of renal osteodystrophy and superimposed osteomalacia that may also result in fractures and low BMD. [bib_ref] Osteopo rosis in renal failure: How accurate is the diag nosis and..., Saadi [/bib_ref] In Stage 1 through 3 chronic kidney disease (CKD), the metabolic changes that accompany early CKD are intermittent hyperphosphotemia and a mild increase of parathyroid hormone. [bib_ref] Definition, evaluation and classification of renal osteodystrophy: A position statement from kidney..., Moe [/bib_ref] Fractures in Stage 1 through 3 CKD are most likely caused by osteoporosis than CKD-related metabolic bone disease. 76 WHO criteria or low trauma fractures for diagnosis of osteoporosis in stage 1 through 3 CKD can be used once other metabolic and biochemical abnormalities have been corrected. [bib_ref] Diagnosis and treatment of osteoporosis in chronic renal failure, Miller [/bib_ref] The current FDA recommendation is to avoid oral bisphosphonates in patients with glomerular filtration rates (GFR) below 35 mL/minute. Pooled data of nine clinical trials showed that residrornate 5 mg/day is safe and effective in osteoporotic women with age-related, mild, moderate or severe renal impairment <30 mL/minute. In all three subgroups, residronate preserved BMD and reduced the incidence of vertebral fractures. The average duration of exposure was 2 years. [bib_ref] Safety and Efficacy of Risdronate in patients with age-related reduced renal function..., Miller [/bib_ref] Similar data about safety and effectiveness of alendronate has been published. Alendronate 5 mg/day was given for first 2 years and 10 mg/day was given for the third year. It reduced vertebrae fractures in patient with GFR down to 15 mL/min. [bib_ref] Alendronate treatment in women with normal to severely impaired renal function: An..., Jamal [/bib_ref] In one trial, raloxifene also increased BMD at both the hip and spine and reduced the risk of vertebral fractures in CKD with the lowest creatinine clearance of 20 mL/minute. [bib_ref] Ensrud KE; MORE Investigators. The effect of Raloxifene treatment in post-menopausal women..., Ishani [/bib_ref] There is also prospective evidence that patients with GFR down to 30 mL/minute gain benefit from oral and intravenous biphosphonate. [bib_ref] Diagnosis and treatment of osteoporosis in chronic renal failure, Miller [/bib_ref] Therefore, recommendations for treatment osteoporosis in stages 1 to 3 CKD: Diagnosis of osteoporosis in Stages 4 through 5 CKD, and in patients on dialysis is complicated by the possible presence of a dynamic bone disease, severe hyperparathyroidism and osteomalacia. They can be associated higher risk for fragility fractures and can mimic osteoporosis. Therefore, the WHO criteria for osteoporosis cannot be used for the diagnosis in CKD when GFR <15 mL/minute or on dialysis, 81 even in the presence of fragility. The diagnosis of osteoporosis in Stages 4 through 5 and in end-stage renal disease (ESRD) can be reliably made only by quantitative bone histomorphometry and/or biochemical markers for bone turnover. Double tetracycline-labeled quantitative histomorphometry can discriminate among the various forms of renal osteodystrophy. Biochemical markers like PTH and bone-specific alkaline phosphatase (BSAP) are helpful. [bib_ref] Diagnosis and treatment of osteoporosis in chronic renal failure, Miller [/bib_ref] An increase in BSAP makes a dynamic bone disease unlikely and osteomalacia or hyperparathorid bone disease more likely. A PTH level <150 pg/ mL is suggestive of low bone turnover. A PTH level 6 times or higher above the upper limit of normal range is associated with high bone turnover. There are no prospective data showing efficacy for any approval pharmacologic agents to treat patients at Stage 4 through 5 and dialysis. [bib_ref] Efficacy and safety of alendronate for the treatment of osteo porosis in..., Bianchi [/bib_ref] Expert opinion suggests that in stages 4 to 5 CKD with fractures, bisphosphonates can be used only after elimination of CKD-related metabolic bone disease. This may require a transiliac bone biopsy. Half of the usual doses of bisphosphonates can be used and the duration is usually not for more than 3 years due to the risk of bone freeze. [bib_ref] Diagnosis and treatment of osteoporosis in chronic renal failure, Miller [/bib_ref] The use of bisphosphonates in dialysis patients with osteoporosis has also never been tested prospectively. Renal excretion is the major route of elimination of these drugs, but intravenous clodronate or ibandronate are removed efficiently from the circulation by dialysis and that the total clearance in hemodialysis patients on a dialysis day is not very different from that in healthy subjects. There is also the risk development or worsening of adynamic bone disease.

## Management of osteoporosis
Important goals in the management of osteoporosis are to prevent fractures, treat pain and discomfort caused by osteoporosis complications, and improve bone density/quality if possible. Non-pharmacologi-

## Who should be treated?
The National Osteoporosis Foundation (NOF) 2008 revised recommendations for treatment are as following: Postmenopausal women or men age > 50 years presenting with: - A hip or vertebral fracture - Osteoporosis with T  -2.5 after excluding secondary causes - A prior fracture and low bone mass (T: -1 to -2.5) - Low bone mass (T: -1 to -2.5) with secondary causes associated with high risk of fracture OR - Low bone mass with 10-year probability 3% of hip fracture or 20% of major osteoporosis related fracture (FRAX) associated disorders - Treating pain, discomfort and other associated morbidity - Increasing bone mass.
In general, there is no cure for osteoporosis, but certain medications may prevent and/or treat osteoporosis. Drugs for osteoporosis primarily reduce bone turnover by inhibiting osteoclast activity. Although they may lead to an early increase in bone mass, the drugs mainly prevent further loss of bone. Agents that primarily increase bone formation (PTH analogs), have also become available and an agent with dual action of anti-resorption and bone formation was also recently introduced (strontium ranelate). Newer therapies are being developed to decrease bone resorption or increase bone formation at targeted molecular levels.

## Pharmacotherapy of osteoporosis
The most commonly used agents in Europe and the US are listed and briefly discussed. 35,82-85 The majority of these agents have been shown to reduce the risk of vertebral fractures. Some have been shown to also reduce the risk of nonvertebral fractures and in some cases specifically at the hip site, . Newer therapies targeting specific molecular sites, calcitonin and Vitamin D derivatives and some other agents are also discussed.

## Selective estrogen-receptor modulators
Selective estrogen-receptor modulators (SERMs) are non-steroidal agents that bind to the estrogen receptor and act as estrogen agonists or antagonists, depending on the target tissue. The concept of SERMs was triggered by the observation that tamoxifen, an estrogen antagonist in breast tissue, is a partial agonist on bone, reducing the rate of bone loss in postmenopausal women. Raloxifene is the only available SERM at present, but several others are in clinical development. Raloxifene prevents bone loss and reduces the risk of vertebral fractures by 30% to 50% in postmenopausal women with low bone mass, with or without prior vertebral fractures as shown in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. [bib_ref] Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with..., Ettinger [/bib_ref] There was no significant reduction of non-vertebral fractures, although in women with severe vertebral fractures at baseline, a post hoc analysis showed a significant reduction of non-vertebral fractures. [bib_ref] Severity of prevalent vertebral fractures and the risk of subsequent vertebral and..., Delmas [/bib_ref] Adverse events rarely included deep venous thromboembolism. There was a significant decrease in the risk of invasive breast cancer that has been subsequently confirmed. [bib_ref] Effects of tamoxifen vs raloxifene on the risk of develop ing invasive..., Vogel [/bib_ref] The concern about increase in cardiovascular events simi-A suggested algorithm to use at KFSHRC based on availability of drugs in the hospital, cost and experience as well as level of evidence is as follows:
- Adequate calcium and vitamin D supplements (cholecalciferol or ergocalciferol) should be provided to all patients. - Alendronate weekly (if no contraindication)
can be used as first-line therapy for treatment of postmenopausal osteoporosis or in elderly males with osteoporosis or for prevention of steroid-induced osteporosis. 109 - Alternative choices for alendronate in postmenopausal osteoporosis are raloxifene for prevention of vertebral fractures as evidence for efficacy against non-vertebral fractures is lacking, or strontium ranelate, for which there is evidence of vertebral and non-vertebral anti-fracture effects. A second-line therapy (considering availability in the hospital, cost and the need for IV administration) is zoledronic acid intravenously as 5 mg dose once yearly in cases where prolonged oral therapy is not feasible or complicated by significant GI side effects or after a hip fracture. [bib_ref] Effect of calcium supplementation on bone loss in post menopausal women, Reid [/bib_ref] - Another second-line therapy is teriparatide (non-formulary medication at KFSHRC) for established osteoporosis with fractures and when there is not an adequate response to bisphosphonates.Treatment should not exceed 2 years and should be initiated after 6 months of alendronate discontinuation. Teriparatide treatment is usually followed by antiresorptive treatment when completed. [bib_ref] A randomized trial of nasal spray salmon calcitonin in postmenopausal women with..., Chestnut [/bib_ref] - Calcitonin should only be used rarely for vertebral osteoporosis and when pain exists and other agents cannot be used. - Treating secondary causes of osteoporosis, and lar to that of conjugated estrogen was addressed in a trial and showed a neutral effect, [bib_ref] Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women, Barrett-Connor [/bib_ref] but it did show an increased risk for venous thromboembolism and gallbladder disease.

## Bisphosphonates
Bisphosphonates have a strong affinity for bone apatite, which is the basis for their clinical use. They are potent inhibitors of bone resorption and produce their effect by reducing the recruitment and activity of osteoclasts and increasing their apoptosis. Oral bioavailability of bisphosphonates is low, between 1% to 3% of the dose ingested, and is impaired by food, calcium, iron, coffee, tea, and orange juice. About 50% of the absorbed bisphosphonate deposits in bone and the remainder is excreted in urine. Their half-life in bone is very prolonged. Alendronate 70 mg once weekly and risedronate 35 mg once weekly are commonly used bisphosphonates.
In the FIT (Fracture Intervention Trial), alendronate reduced the incidence of vertebral, wrist, and hip fractures by approximately half in women with prevalent vertebral fractures. [bib_ref] Randomised trial of effect of alendronate on risk of fracture in women..., Black [/bib_ref] In women without prevalent vertebral fractures, there was no significant decrease in clinical fractures in the overall population, but the reduction was significant in the one-third of patients that had a baseline hip BMD T-score lower than -2.5 SD. [bib_ref] Effect of alendronate on risk of fracture in women with low bone..., Cummings [/bib_ref] Risedronate has been shown in women with prevalent vertebral fractures to reduce the incidence of vertebral and non-vertebral fractures by 40% to 50% and 30% to 36%, respectively. [bib_ref] Effects of risedronate treatment on vertebral and nonver tebral fractures in women..., Harris [/bib_ref] In a large population of elderly women, risedronate decreased significantly the risk of hip fractures (by 30%), an effect that was greater in osteoporotic women aged 70-79 years (40% reduction). [bib_ref] Effect of risedro nate on the risk of hip fracture in elderly..., Mcclung [/bib_ref] Ibandronate given daily (2.5 mg) reduces the risk of vertebral fractures by 50% to 60%, [bib_ref] Randomised trial of effect of alendronate on risk of fracture in women..., Black [/bib_ref] whereas an effect on non-vertebral fractures was only demonstrated in a post hoc analysis of women with a baseline of BMD T-score below -3 SD. [bib_ref] Daily and intermittent oral ibandronate normalize bone turn over and provide significant..., Delmas [/bib_ref] Comparative and pooled (bridging) studies have shown that oral ibandronate 150 mg once monthly or intravenous ibandronate 3 mg every 3 months are equivalent or superior to daily ibandronate in increasing BMD and decreasing biochemical markers of bone turnover, giving rise to their approval for the treatment of postmenopausal osteoporosis. [bib_ref] Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year..., Reginster [/bib_ref] [bib_ref] Intra venous ibandronate injections in postmenopausal women with osteoporosis: One-year results from..., Delmas [/bib_ref] The efficacy of yearly infusions of zoledronate 5 mg over three years was assessed in postmenopausal women in a placebo controlled fashion (HORIZON study [Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly]). [bib_ref] Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis, Black [/bib_ref] Zoledronate was found to reduce the incidence of vertebral fractures by 70% and that of hip fractures by 40%. Intravenous zoledronate has also been shown to decrease the risk of mortality when given shortly after a first hip fracture. [bib_ref] The HO-RIZON Recurrent Fracture Trial: Zoledronic acid and clinical fractures and mortality..., Lyles [/bib_ref] The overall safety profile of bisphosphonates is favorable. Oral bisphosphonates are associated with mild gastrointestinal disturbances, and rarely cause esophagitis and ulcer. A recent study also showed an increase in esophageal cancer among chronic users. Intravenous zolendronate can induce a transient acute phase reaction with fever, bone and muscle pain that ameliorates or disappears after subsequent courses. Osteonecrosis of the jaw has been described in cancer patients receiving high doses of intravenous pamidronate or zoledronate. Atrial fibrillation was noted to occur in a higher frequency after intravenous zolendronate, but a causeeffect relationship was not established and it was not seen in another study.
The parathyroid hormone analogs Intermittent administration of PTH (for example, with daily subcutaneous injections) results in an increase of the number and activity of osteoblasts, leading to an increase in bone mass and in an improvement in skeletal architecture at both cancellous and cortical skeletal sites. The 1-34 N-terminal fragment (teriparatide) is used for the management of osteoporosis. Treatment with teriparatide has been shown to reduce significantly the risk of vertebral fractures and to reduce non-vertebral but not hip fractures. [bib_ref] Effect of parathyroid hormone (1-34) on fractures and bone mineral density in..., Neer [/bib_ref] The recommended dose is 20 g of teriparatide daily, given as a subcutaneous injection. The effect was initially seen in patients with severe osteoporosis and established vertebral fractures. Efficacy was later shown with osteoporosis even without fractures. [bib_ref] Parathy roid hormone (1-84) and treatment of osteoporo sis, Ahrader [/bib_ref] The most common reported adverse events in patients treated with teriparatide are nausea, pain in the limbs, headache and dizziness. In normocalcemic patients, slight and transient elevations of serum calcium concentrations have been observed following the injection of teriparatide. The change is small and routine monitoring of serum calcium during therapy is not required. Teriparatide may cause small increases in urine calcium excretion, but the incidence of hypercalciuria does not differ from that in placebo-treated patients. However, these agents should be used with caution in patients with active or recent urolithiasis. Isolated episodes of transient orthostatic hypotension are also reported. The use teriparatide is contraindicated in conditions with increased bone turnover (for example, pre-existing hypercalcemia, metabolic bone diseases other than primary osteoporosis, including hyperparathyroidism and Paget disease of bone, unexplained elevation of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton or in patients with skeletal malignancies or bone metastasis). Severe renal impairment is also a contraindication.

## Strontium ranelate
Strontium ranelate is a recently approved agent in Europe, for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral and hip fractures. There is some evidence that strontium ranelate both inhibits bone resorption and stimulates bone formation, suggesting that the agent may uncouple the bone remodelling process. Studies conducted up to 5 years have shown fracture efficacy of strontium ranelate, at spinal and non-vertebral sites, in a wide range of patients. [bib_ref] Effects of long term strontium ranelate treat ment on the risk of..., Reginster [/bib_ref] Modest reduction in hip fracture rates has also been shown in women over the age of 74 years with low bone density at the femoral neck. [bib_ref] Strontium ranelate reduces the risk of nonver tebral fractures in postmenopausal women..., Reginster [/bib_ref] The recommended daily dose is a one 2-gram sachet once daily by mouth. The absorption of strontium ranelate is reduced by food, milk and its derivative products and the drug should be administered, therefore, between meals. Ideally, it should be taken at bedtime, preferably two hours after eating. Strontium ranelate is not recommended for patients with severe renal impairment (creatinine clearance below 30 mL/min).
The most common adverse events are nausea and diarrhea, which are generally reported at the beginning of treatment and usually disappear after the third month of treatment. An increase in the incidence of venous thromboembolism (relative risk 1.42) has been reported when pooling all phase III studies in osteoporosis. Therefore, strontium ranelate should be used with caution in patients at increased risk of venous thromboembolism, including those with a past history. Hypersensitivity reactions have also been reported rarely with this agent. The effects of the major pharmacological interventions on vertebral and hip fracture risk are summarized in of the appendix.

## Combination and sequential treatments
The combination of two inhibitors of bone resorption may result in a further decrease in bone resorption and a greater increase in BMD. Whether this results in a better effect on fracture risk, however, has not been adequately addressed or proven. If low doses of hormone replacement treatment (HRT) are used for a limited period of time for the management of climacteric symptoms, concomitant use of bisphosphonates may provide an appropriate reduction in bone turnover that may not be achieved with low doses of HRT alone. [bib_ref] Is there any interest in com bining treatments in osteoporosis?, Rabenda [/bib_ref] Patients pre-treated with inhibitors of bone resorp-tion, who have not achieved a full therapeutic response, are good candidates for treatment with anabolic agents. The increase in bone turnover that follows the introduction of teriparatide in patients treated with an anti-resorptive agent is similar to that observed in treatment-naive patients as is the pattern of response in BMD, with the exception of a six-month delay in the increase in spinal and hip BMD in patients previously exposed to alendronate. An important question is whether the combination of an anti-resorptive agent and an anabolic drug, such as teriparatide, would provide a therapeutic advantage. In a published study, there was no evidence of synergy between teriparatide and alendronate, and the changes in the density and cortical volume suggested that the concurrent use of alendronate may reduce the anabolic effects of teriparatide. [bib_ref] The effects of parathyroid hormone and alendronate alone or in combination in..., Black [/bib_ref] The apparent absence of synergistic effect of teriparatide and alendronate should not obscure the potential benefit of using an inhibitor of resorption after treatment with teriparatide. Indeed, there are data that suggest that the administration of an inhibitor of resorption (bisphosphonate or SERM) after treatment with teriparatide maintains or even potentiates the skeletal benefit observed during teriparatide treatment. 107

## Other pharmacological interventions

## Calcitonin
Calcitonin is a hormone that inhibits osteoclastic bone resorption. Salmon calcitonin is approximately 40-50 times more potent than human calcitonin, and the majority of clinical trials have been performed with salmon calcitonin. For clinical use it can be administrated either by injection or nasal application, which provides a biological activity of 25% to 50% compared with the injectable formulation. Calcitonin modestly increases bone mineral density at the lumbar spine and forearm. It may reduce the risk of vertebral fracture; however, the magnitude of the impact on these fractures remains questionable. Overall there seems to be no effect on non-vertebral fractures. [bib_ref] A randomized trial of nasal spray salmon calcitonin in postmenopausal women with..., Chestnut [/bib_ref] Because of its cost and limited and modest effect, routine use is not recommended. The analgesic properties may, however, be an interesting option for acute pain following a spinal fracture.

## Hormone replacement therapy
Estrogens reduce the accelerated bone turnover induced by menopause and prevent bone loss at all skeletal sites regardless of age and duration of therapy. Results from observational studies and randomized placebo controlled trials have shown that estrogen decreases the risk of vertebral and non-vertebral fractures (including hip fracture) by about 30%, regardless of baseline BMD. When HRT is stopped, bone loss resumes at the same rate as after the menopause, although fracture protection may persist arguably for several years.The results of the Women' s Health Initiative (WHI)suggests, however, that the long-term risks of HRT outweigh the benefits. In this large cohort of postmenopausal women in their 60s, the combined use of conjugated estrogen and medroxyprogesterone acetate was associated with a 30% increased risk of coronary heart disease (CHD), and breast cancer and with a 40% increase in stroke. There was also a slight increase in the risk of dementia. In hysterectomized women receiving conjugated estrogen alone, there was also a significant increase in stroke, but not of CHD and breast cancer, suggesting a deleterious effect of medroxyprogesterone acetate. Whether the benefits of HRT would outweigh the risks with other estrogen and progestin and in younger postmenopausal women is debated, but so far there is no placebo-controlled study showing the long-term safety of such alternatives. In most countries HRT is only recommended for climacteric symptoms, at a dose as small as possible and for a limited period of time. Thus, HRT is no longer recommended as a first line treatment for the prevention and treatment of osteoporosis.

## Vitamin d derivatives
Both alfacalcidol (25 OH vitamin D3) and calcitriol (1,25 (OH)2 Vitamin D3) are used by some for the treatment of osteoporosis. Several but not all studies show decreases in vertebral fracture risk. [bib_ref] One year alendronate after one year of parathyroid hormone (1-84) for osteoporosis, Black [/bib_ref] The effects on bone mineral density have been less extensively studied. A few reports have suggested that alfacalcidol and calcitriol exert a direct action on muscle strength and decreases the likelihood of falling in elderly subjects. [bib_ref] Effect of calcium supplementation on bone loss in post menopausal women, Reid [/bib_ref] The major problem with the use of the vitamin D derivatives is the risk of hypercalcaemia and hypercalciuria. Most guidelines recommend against using active vitamin D (one alpha or calcitriol) in the treatment of osteoporosis without clear indication of renal failure or vitamin D synthesis defects or other clear indications.

## Newer therapies
Newer therapies continue to be developed and introduced for the management of osteoporosis. They can be divided into drugs with improved formulation and potency such as zoledronic acid with once yearly intravenous administration and ibandronate with once monthly oral administration or quarterly intravenous administration. These drugs could provide better adherence and compliance to therapy. Drugs with newer therapy targets that improve bone formation include teriparatide and strontium ranelate. They appear to have a dual action of improving bone formation and slowing down bone resorption. Other therapies under evaluation have a specific molecular target resulting in decreasing bone resorption or enhancing bone formation. Osteoclasts are bone-forming cells that control the differentiation of osteoclasts into active cells, through a certain molecule called RANK ligand (RANKL) that binds to the RANK receptors on osteoblasts. Osteoprotegrin (OPG) is also secreted from osteoblasts and block the RANKL-RANK interaction, therefore decreasing osteoclasts differentiation.
Denosumab, a new drug under evaluation, acts as an anti-RANKL blocking osteoblast differention and slowing bone resorption similar to the OPG. Other drugs under investigation are the cathepsin K inhibitors, that inhibit cathepsin K, which is an enzyme secreted by osteclasts to increase bone resorption. Newer bone forming agents are alson in development. The action of osteoblasts is regulated by special proteins called Wnt that interact with special receptors on the surface of osteoblasts called LRP5 and LRP6. This interaction stimulates the activity of osteoblasts in bone formation through intracellular factors like axin and B-catenin. Sclerostin is a factor that blocks the interaction of Wnt with LRP receptors, slowing bone formation. A new drug under testing is an antisclerostin antibody that would therefore increase bone forming activities of the osteoblast. [bib_ref] New and emerging treatment for osteoporosis, Clarke [/bib_ref] These and other drugs under investigation, could present a new front for the management of osteoporosis in the near future.

## Choice of therapy and suggested algorithm at kfshrc
With the wide availability of different therapies and the development of even more therapies in the future, the choice of therapy may become more difficult for practitioners. However, like many other chronic diseases, alternative therapies provide more flexibility and individualized choices. There are, however, certain criteria and basic rules for the choice of treatment that practicing physician needs to take in account, including the level of evidence for efficacy of a certain agent. Trials on different therapeutic agents have been done. Randomized controlled trials (RCTs) or metanalyses of a number of RCTs for a specific agent are considered of highest value. Comparison between agents, however, is not possible based on those studies because of different populations and therefore different risks for fractures. Direct Assess need for therapy at 3-to 6-month intervals a Before prescribing estrogen therapy to postmenopausal women, all non-estrogen preparations should be considered first. The risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals.
[fig] Figure 1: Prevalence of osteopenia and osteoporosis in a study of 321 healthy Saudi women based on lumbar spine BMD.12 [/fig]
[fig] : All patients should receive recommended dose of calcium if no contraindication. All patients should receive recommended the dose of vitamin D. A vitamin D level should be checked in addi-tion to PTH and other markers like alkaline phosphatase to rule out renal-induced metabolic bone disease. In stages 1-3 CKD, oral and intravenous bisphosphonates are probably safe if indicated. [/fig]
[fig] Appendix 4: Calcium content of foods. [/fig]
[table] Table 2: Proximal femur annual fracture rates per 100 000 population in Saudi subjects seen in Riyadh region (from Nuaim et al with permission).17 [/table]
[table] Table 1: Prevalence of osteopenia and osteoporosis in Saudi population (>50 years) and in US/European population (from reference 14, with permission). [/table]
[table] Table 3: World Health Organization definition of osteoporosis. [/table]