Osteoporosis - In-Depth Overview for Physicians

1. Definition
2. Pathogenesis
3. Clinical Presentation
4. Laboratory Findings
5. Differential Diagnosis
6. Initital Treatment
7. Long-term Management issues
8. Prognosis
9. When to Refer

Definition

Osteoporosis is a disorder of low bone mass, microarchitectural deterioration, bone fragility and increased susceptibility to fracture. Patients often develop a thoracic kyphosis.

Thoracic Kyphosis

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There is a clear difference between normal bone:

Normal Bone

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Osteoporotic Bone

Low bone mass is the most accurate predictor for increased fracture risk. It is estimated that one of every two Caucasian women will experience an osteoporotic fracture at some point in her lifetime. The risk for men is lower, but increases with age. All ethnicities are affected. World Health Organization (WHO) criteria estimate that 15% of all Caucasian women in the U.S., and 35% of women over 65 years have osteoporosis[1]. The lifetime risk of hip fracture in white women is similar to the combined risk of breast, endometrial and ovarian cancer.

The Impact of Osteoporosis[2]

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The impact on public health is enormous. In the United States, an estimated 1.5 million fractures each year, are attributed to low bone mass[3]. The majority of fractures are vertebral. One-third are symptomatic and the remainder are note incidentally on radiographs. Annually, there are about 700,000 vertebral fractures, 250,000-275,000 hip fractures[4],[6] and 250,000 wrist fractures[5]. The incidence of osteoporotic fractures increases with age, and is more common in women than men. Despite advances in the treatment of hip fractures, mortality within the first year of fracture remains in excess of 15-20% and less than one-third of patients are restored to their functional status prior to the fracture. Some estimates indicate a new hip fracture costs greater than $40,000[6].

Pathogenesis

Humans reach their peak bone mass in the 3rd or 4th decade. Thereafter, men lose density at a slow, steady pace (0.3-0.5%/yr) throughout their lives. Women lose density at this same pace until menopause, when they begin to lose 2-3% per year for approximately 10 years, and then resume a rate of loss comparable to men.

Changes in Bone Mass with Growth

This is a result of bone resorption by osteoclasts, outstripping bone formation by osteoblasts. Pits are created by osteoclasts and, after the age of 40, osteoblasts are unsuccessful in completely filling the pits. Trabecular bone (i.e. vertebral body, hip) is affected more than cortical bone, due to its greater surface area. The actual dimensions of the trabeculae decrease and more importantly, trabeculae struts lose their connectivity. There is also cortical thinning. This results in decreased strength of the bone, and a greater propensity to fracture.

It is important to maintain an adequate supply of calcium and Vitamin D throughout one's life so that peak bone mass can be achieved and maintained. Hyperparathyroidism, at times due to inadequate calcium absorption or increased excretion, has a negative effect on calcium balance and promotes bone resorption. Hyperthyroidism also promotes bone resorption. Both estrogen and testosterone help achieve and maintain peak bone mass. A deficiency of either hormone will contribute to reduced bone mass. Lack of mechanical load and its bone-stimulating actions results in a reduced bone mass, and any state of reduced activity will demonstrate this effect. Of note is the observation that exercise resulting in amenorrhea will have a negative impact on bone density. This has been shown in runners by Drinkwater[7]. Warren[8] has shown that adequate calories are more important that restoring menstrual cycles.

Many drugs contribute to bone loss. The most common cause of drug-induced osteoporosis is corticosteroids. Corticosteroids hinder the action of osteoblasts. In addition, corticosteroids cause hypercalciuria and decreased absorption of calcium in the gut. This results in hyperparathyroidism and increased bone resorption. Other drugs implicated in bone loss include heparin, excess thyroid replacement, and anticonvulsants.

Causes of Decreased Bone Mass

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Clinical Presentation

All too often the patient's first sign of osteoporosis is a fragility fracture. At times, this may be obvious, but more than 65% of individuals with a compression fracture will be asymptomatic[9]. As patients with low bone mass are asymptomatic until a fracture occurs, it is the job of the health care provider to prophylax against osteoporosis and to suspect osteoporosis and evaluate with bone density testing.

Bone mass can be determined by a number of methods. The most commonly used technique is dual energy xray absorptiometry (DEXA). The amount of mineralized tissue within a section of spine or hip is measured and expressed as grams per cm2. Values are compared to sex- and aged-matched controls (Z Score) or to healthy, same sex individuals aged 35 years who are felt to have attained peak bone mass (T Score).

The World Health Organization (WHO) has established criteria for the diagnosis of osteoporosis. If the individual is within one standard deviation of peak bone mass (T score), she or he is considered to have normal bone density. If bone mass is between one and 2.5 standard deviations below peak bone mass (T score), osteopenia is diagnosed. If bone mass is 2.5 standard deviations below peak bone mass (T score), osteoporosis is diagnosed. If the patient has also had a fragility fracture, severe osteoporosis is diagnosed.

Risk factors for osteoporosis have been established. Major risk factors include: family history of osteoporosis or fragility fractures, fragility fracture at an age less than 45 years old, weight less than 127 lbs., and current tobacco use. Minor risk factors include: Caucasian women more than 65years, estrogen deficiency, low calcium intake, alcoholism, sedentary life style, and certain chronic diseases, such as rheumatoid arthritis, malabsorption syndromes, Marfan's Syndrome, hyperthyroidism, and hyperparathyroidism. Osteoporosis should also be considered if more that two inches of height are lost or if there is a thoracic kyphosis. Scoliosis is associated with osteoporosis. Although osteoporosis is traditionally felt to be a disease of Caucasian women, recent studies have demonstrated that both Asian and Latino women are at risk, as well as up to 15% of Afro-American women.

Laboratory Findings

Standard roentgenograms do not provide accurate information for the diagnosis of osteoporosis. When osteoporosis is suggested on standard roentgenograms, perhaps 40% of bone mineral has already been lost. The appendicular skeleton is composed primarily of cortical bone, while the axial skeleton is composed of a combination of cortical bone (vertebral endplates and posterior elements) and trabecular bone (vertebral bodies). The metabolic rate of trabecular bone is greater than cortical bone and it has greater surface area than cortical bone; as a result, bone loss is for the most part first detected in trabecular bone. There are a few exceptions. In hyperparathyroidism, bone loss may be greater in cortical bone. Recent studies using quantitative computerized transaxial tomography (QCT) suggest that in the radius, subcortical bone may be lost earliest in women aged 45-55 years[10].

Bone mineral density testing is indicated for anyone at risk for osteoporosis. Axial DEXA is considered the gold standard for measuring bone mineral density. It has a precision of +/- 3% and is used for both diagnosis and to follow treatment. Lumbar spine and hip measurements are most commonly obtained. In order to follow density results over time, it is best to use the same machine i.e. Hologic or Lunar. This is because although the T-score is comparable, the actual density reading may not be comparable.

There are alternative methods available to measure bone density. These include: axial and peripheral CT, peripheral dual energy absorptiometry, and peripheral quantitative ultrasound densitometry, Peripheral modalities can measure bone density in the forearm, finger, shin and heel. The peripheral modalities are felt to have a 0.75 correlation, at best, with axial readings. However, the machines are portable, and as such, they are felt to be modalities for screening. If osteoporosis is suspected, a DEXA should be obtained. DEXA is also used to monitor treatment. A recent review examines the various modalities available for the diagnosis of osteoporosis[11].

The Bone Mass Measurement Act became effective July 1, 1998[12]. This act details justification for reimbursement. The regulation is somewhat ambiguous but approves testing for estrogen-deficient women at risk for osteoporosis.

Bone Mass Measurement Act

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Other indications for testing include: an individual with a vertebral abnormality suggestive of fracture, an individual receiving glucocorticoid therapy (more than 7.5mg/d, for more than 3mos.), an individual with hyperparathyroidism, and an individual being monitored on an FDA-approved treatment for osteoporosis. An astute clinician would be wise to obtain a bone mineral density measurement on anyone at risk for osteoporosis. The National Osteoporosis Foundation recommends obtaining a bone density measurement on anyone with a fragility fracture. Consideration should also be given to anyone with an early menopause, anyone with a medical condition or use of a drug that is known to predispose to osteoporosis. As technologies become more accessible, it would be hoped that bone mineral density testing would be a routine part of preventative health care.

Bone density measurements provide information about the current skeletal mass, but does not provide information about metabolic activity. This is extremely important. Bone is in a constant state of flux. Osteoblasts are bone-forming cells that form osseous matrix. Osteoclasts are bone-resorbing cells that break down matrix. Markers of bone formation include osteocalcin, bone alkaline phosphatase and the C- and N-terminal propeptides of type 1 collagen. Markers of bone resorption include urine and serum N-telopeptide, urine C-telopeptide, pyridinoline and deoxypyridinoline. The most commonly used marker to assess bone turnover is the urine N-telopeptide, although the serum N-telopeptide assay is becoming increasingly available.

A large number of studies have shown a relationship between the level of various bone markers and the associated prediction of future bone mineral density measurements. Various investigators have should that for a 1 SD increase in a bone marker value above that of a premenopausal women, there is a 1.5 to 2.5-fold increase in bone loss over the next year[13],[14]. In a practical sense, the higher the bone marker i.e. urine NTX value, the greater the risk of bone loss over the next year. For most commercial laboratories, a urine NTX level above 35-50nM BCE/mM creatinine is suggestive of ongoing bone loss. The goal in a patient with osteoporosis is to drive the NTX below these values, to a NTX seen in premenopausal women. Bone markers have also been shown to predict fracture risk. The risk of fracture is greater in states of high bone turnover. Interestingly, the risk of fracture is similar in patients with low vertebral bone mass and in those with high bone turnover. In the EPIDOS study, Garnero et al. reported that each 1 SD increase in C-telopeptides or free deoxypyridinoline values was associated with a 1.3- or 1.4-fold increase in hip fracture[15]. Bone markers can also be used in assessing the differential diagnosis of osteoporosis. Markedly elevated markers of bone resorption can be seen in conditions such as hyperthyroidism, hyperparathyroidism, Paget's Disease, multiple myeloma, hypercalcemia of malignancy, and bone metastatic disease. Lastly, bone markers can be used to monitor therapy. Within 3-6 months of beginning a successful treatment, the bone resorptive marker should decrease. This has been demonstrated for HRT, bisphosphonates, calcitonin, and the selective estrogen receptor modulators. If a reduction in bone marker is not observed, one should reassess patient compliance, consider other diagnoses leading to bone loss, and consider a change in therapy.

Unfortunately, current bone markers are not completely accurate. There is a circadian rhythm to bone resorption, with bone resorption being increased at night. To maximize reliability, the urine NTX specimen should be the second voided urine. Blood in the urine will interfere with testing. Although prohibitive secondary to cost, an average of several samples would be most representative of true bone turnover. Automated assays for urine NTX should improve testing; these are increasingly used. Serum NTX testing, which is becoming more commonly available will eliminate inaccuracies due to the correction for creatinine in urine samples.

Differential Diagnosis

If a Z-score is more than 1.5 standard deviations below expected, secondary causes of osteoporosis must be investigated. Testing should be tailored to each individual. Tests help investigate various causes of osteoporosis including inflammatory conditions, hyperparathryroidism, hyperthyroidism, vitamin D deficiency, multiple myeloma, and osteomalacia. Tests to be considered include ESR, serum calcium, serum phosphate, alkaline phosphatase, 25- Vitamin D, serum and urine immunoelectrophoresis, PTH level, and TSH level. It may be rewarding to identify a secondary cause of osteoporosis, as treatment of this condition may improve bone density and hopefully bone strength. A recent study evaluating the treatment of hyperparathyroidism, revealed an 8% increase in bone density one year after parathyroidectomy, and a 12% increase after 12 years[16]. It is common to be unable to identify a cause of osteoporosis. The vast majority of these individuals may have risk factors including: family history of osteoporosis or fragility fractures, reduced calcium intake, especially prior to development of peak bone mass, and sedentary lifestyle.

Initial Treatment

a. Calcium/Vitamin D

All patients with bone loss or the potential for bone loss should be educated on the appropriate intake of calcium and vitamin D. These guidelines have recently been revised. Both the NIH,and the NOF, have published guidelines. Infants should obtain 400-600mg per day of calcium, and children 800mg per day.

NIH Guidelines for Calcium Intake

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Adolescents should obtain 1200-1500mg per day of calcium. Premenopausal women should obtain 1000mg per day and postmenopausal women should obtain 1000-1500mg per day of calcium. Men under 65years should obtain 1000mg per day and men over 65 years should obtain 1500mg per day. The recommended daily intake of Vitamin D is 400-800 I.U and 600-800I.U, in the elderly. Calcium and Vitamin D supplementation is necessary if diet is inadequate. Calcium and vitamin D will decrease bone resorption and mineralize osteoid. Many studies have addressed the intake of calcium and Vitamin D and the effect on both bone density and fracture. Particularly in nursing home populations, calcium and vitamin D have been associated with a decrease in the hip fracture rate. Chapuy has shown that the use of calcium and vitamin D decreases hip fractures by 25%[17].

Recommended Calcium Intake

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Several studies have demonstrated that patients taking adequate calcium and vitamin D have higher bone mass. Calcium and Vitamin D will not prevent spinal bone loss in women who are perimenopausal. Conversely, the appendicular skeleton will be maintained in all age groups in woman who are premenopausal and elderly women who obtain physiologic levels of calcium and Vitamin D coupled with adequate exercise. In patients taking glucocorticoids, adequate calcium and vitamin D preserves bone density. The use of calcium and vitamin D without antiresorptive therapy limits the ability to increase bone density in either postmenopausal women or in patients on glucocorticoids.

The two most available forms of calcium include: calcium carbonate and calcium citrate. Either type is an acceptable replacement. Some evidence supports better absorption of calcium citrate. This preparation may be a more judicious choice in patients with achlorhydria or nephrolithiasis. It can be taken with or without meals. Calcium carbonate is better absorbed with meals, as is requires an acid stomach for maximal absorption. There are many sources of supplemental Vitamin D. Multivitamin tablets and vitamin D supplements usually contain 400IU of Vitamin D. Many calcium supplements contain Vitamin D.

Most authorities including the National Osteoporosis Foundation (NOF) recommend the addition of antiresorptive therapy if the T score is -1.5 SD or greater with major risk factors for fracture, or - 2.0 SD or greater without risk factors. Major risk factors include patients with a personal history of fracture, a first degree relative with a fragility fracture, tobacco use, and body weight less than 127 lbs.

Of course decisions about treatment must be made based on each individual's bone density and his/her associated medical conditions. Factors to consider include the menopausal status, the degree of bone turnover, i.e. an elevated NTX value, concomitant medical illnesses, the use of medications contributing to bone loss, and the patient's level of activity. If there is reason to believe that the patient is at risk for imminent bone loss, the use of antiresorptive therapy should be strongly considered. It is well established that the use of glucocorticoids is associated with rapid bone loss during the first 3 months of therapy, thereafter the rate of loss slows somewhat. As soon as a decision is made to use glucocorticoid for more than 2 weeks, a plan to combat osteoporosis should be initiated.

b. Bone-formation agents

To date, we have not had clinically useful agents that promote bone formation. The use of sodium fluoride was generally disappointing, as it was associated with an increase in fracture rate and osteomalacia. Parathyroid hormone is expected to gain FDA-labeling for the treatment of osteoporosis. It has been shown to increase bone density and prevent fractures in both postmenopausal women and in-patients on corticosteroids. It will most likely be used in combination with an antiresorptive agent. Data presented at Osteoporosis: World Congress 2000 by Cosman demonstrated that PTH (1-34) used in combination with HRT revealed a 12.8% increase in spine density and a 4.4% increase in hip density. There was a statistically significant reduction in fracture rate. Studies done for the treatment of glucocorticoid-induced osteoporosis have demonstrated an 11% increase in lumbar bone density during a one-year study period (18). Parathyroid hormone increases both bone formation and bone resorption, but the net effect is an increase in bone density. It is given subcutaeously, as a daily injection. To date, side effects have been minimal. Studies to date with anabolic steroids have demonstrated too many virilizing effects[18].

c. Antiresorptive agents

1. Bisphosphonates

Given the absence of agents resulting in bone formation, treatment has focused on agents decreasing bone resorption. The agents most studied include the bisphosphonates. Etidronate, a first generation bisphosphonate has been shown to increase BMD and reduce vertebral fracture rate, but has been associated with osteomalacia. This is less of a concern for the newer bisphosphonates. Alendronate and risedronate are oral bisphosphonates approved for the treatment of osteoporosis. Alendronate has been shown to increase spine BMD by 8% and hip BMD by 5% at 3 years[19]. It decreases hip fracture by 51% and vertebral fractures by 47%[20]. It has an increased incidence of esophageal irritation, perhaps in up to 30% of individuals, although premarketing studies suggest there is no increased incidence compared to placebo.

Studies with risedronate reveal fairly similar fracture and BMD data. Direct head-to-head studies between these two agents have not been done and the available studies are not precisely comparable. Over a 3-year period, risedronate treated patients had a BMD increase of 5.4% in the lumbar spine and 1.6% in the femoral neck. The rate of new vertebral fractures was reduced by 41%, and the rate of new nonvertebral fractures was reduced by 39%[21]. Premarketing studies indicate there is not increase in gastointestinal irritation compared with placebo; this was also true for alendronate. Both agents have been shown to prevent corticosteroid-induced bone loss.

The dose of alendronate originally approved for the prevention of osteoporosis was 5mg daily and for the treatment of osteoporosis was 10mg daily. More recently, a dose of 70mg weekly has been approved for the treatment of osteoporosis. Efficacy and toxicity seem comparable to the originally approved dose. Most patients find the weekly dose more suitable, which increases compliance. The dose of risedronate for the treatment and prevention of osteoporosis is 5mg per day or 35mg per week. The weekly dose was recently FDA-approved. The use of bisphosphonates in women prior to childbearing has not been well studied. The use of these agents in this population should be weighed against the potential benefits. Bisphosphonates are often an excellent choice for the treatment of men with osteoporosis, and a recent study has demonstrated efficacy, in this regard.

Although not FDA-approved for the treatment of osteoporosis, pamidronate has been fairly well studied in the treatment of osteoporosis. It increases BMD and decreases fracture rate. Most studies has given 30mg IV every 3 months. Occasionally, flu-like symptoms are noted after the infusion. This can often be managed with pretreatment with diphenhydramine and acetaminophen. Over the next several years, other intravenous bisphosphonates are likely to be approved for the treatment of osteoporosis. Zoledrondric acid (Zometa) is approved for the treatment of hypercalcemia of malignancy; studies are underway for its use in osteoporosis. The proposed yearly dose will probably be 4mg IV over 45 minutes. In general bisphosphonates are safe and well tolerated. They increase BMD and reduce fracture rate.

2. Hormone replacement therapy

Hormone replacement therapy(HRT) and the effect on bone health has not been studied with the same methodological rigor as with the newer available agents. Estrogen in the form of Premarin 0.625 mg (Wyeth-Ayerst Laboratories, Philadelphia, PA) has been studied in the treatment and prevention of osteoporosis. It will increase bone mass by 2% per year. In nonrandomized trials, it has been shown to decrease fracture rates at all sites by 50%. Conflicting data make it unclear if a dose of 0.3mg is sufficient to both prevent and treat osteoporosis. It may be that in some women i.e. due to weight, etc. that this dose is sufficient. The use of estrogen for the treatment of osteoporosis must be weighed against the possible risks. Use of HRT does increase the risk of breast cancer, especially after 10years of use. The increased risk seems to be 2%/yr of use. HRT is associated with an increased incidence of thrombosis, and if used without progesterone, an increased incidence of uterine cancer. HRT improves cholesterol values and the lipid profile, but recent data suggests it may increase the risk of myocardial infarction in someone with unstable coronary artery disease. The estrogen/progesterone arm of the Women's Health Initiatives Study was recently halted early due to an excess number on cardiovascular and thrombotic events. However, there were fewer hip fractures in the estrogen/progesterone treated women, compared to those on placebo. The estrogen only arm was not halted.

3. Selective estrogen receptor modulators

The selective estrogen receptor modulators (SERMs) are a new class of agents that includes tamoxifen and raloxifene. Raloxifene increases BMD in the spine by 3%, over 3 years. It decreases vertebral fracture by 40%[22]. No benefit has yet been demonstrated in reducing hip fractures. Therefore, the SERMs are less effective than estrogen and the newer bisphosphonates in increasing bone mass and preventing fracture. These agents can precipitate menopausal symptoms, but they do reduce the risk of breast cancer, a marked concern for many women. There is no increased risk of uterine cancer. The benefit on lipids is favorable, although not as beneficial as with HRT.

4. Calcitonin

Calcitonin in available in a nasal spray. Side effects including nasal irritation are rare. The dose is 200 I.U. intranasally each day, alternating nostrils. It is the least effective antiresorptive agent. It is indicated for patients who cannot, or prefer not to take other agents. It increases spine BMD and reduces spine fractures by 37%. No benefit has been noted in the hip. Limited data suggests that it may reduce pain associated with an acute fracture. There is a 2% risk of epistaxis, which is usually minor. If the T-score is less than -2.5 S.D., combination therapy should be considered. Bone has shown that alendronate and estrogen produced larger increases in BMD than either agent alone and is well- tolerated[23]. The use of bisphosphonates and raloxifene has not been well studied, but perhaps the combined effect would be advantageous to increased bone density. Treatment is summarized in Table 10.

The Treatment of Osteoporosis

5. Falls Prevention/Exercise

The loss of muscle mass, flexibility, and balance occurs almost universally in the aging, and these losses are accompanied by an increase in the frequency of falls. If falls can be prevented, a significant number of fragility fractures can be avoided. The living environment should be carefully reviewed with this goal in mind. Lighting, especially at night should be adequate. Rugs should be secured to the floor. The use of sedating medications should be kept to an absolute minimum. Exercise programs that promote mobility, muscle strengthening, balance, and flexibility should be emphasized. Tai Chi is an exercise program that meets many of these goals[24]. For maximum benefit, it should be practiced regularly. It is well tolerated by the population at risk. Classes are more readily available.

6. New Advances: Vertebroplasty/Kyphoplasty

Recently several new techniques have become available to treat vertebral fractures. Vertebral fractures can be extremely painful. In addition, their effect on posture, overall mobility, and cardiopulmonary function can cause marked morbidity. New techniques have been designed to correct vertebral fractures. Vertebroplasty involves injecting cement directly into fractured vertebral bodies.

Vertebroplasty: Procedure to Restore Stability

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This has been shown to decrease pain, increase mobility and improve spine stability. There is no effect on fracture reduction or deformity. The technique is still fairly new and there can be a 6% complication rate per level. Kyphoplasty involves using an inflatable bone tamp to inject bone void filler under low pressure into the involved vertebral body.

Thoracic Kyphosis

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Kyphoplasty: Procedure to Reduce Kyphosis and Restore Stability

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Kyphoplasty 2


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Kyphoplasty 3

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The fracture may be reduced. There is rapid relief of pain. The procedure seems well-tolerated. Both of the procedures are available at The Hospital for Special Surgery.

Long-Term Management Issues

If the bone marker remains elevated despite what appears to be an adequate regiment for the treatment of osteoporosis, consideration must be given for secondary causes of osteoporosis. Appropriate lab evaluation can be performed. Some patients appear to respond more to one agent or another i.e. HRT or a bisphosphonate. In this instance, changing the regiment and following a bone marker would be helpful. At times patients appear to fracture with a relatively normal bone density. One then worries about the quality of the bone. In addition to a metabolic work-up, a bone biopsy with tetracycline labeling may be indicated.

Prognosis

With regard to BMD, a loss of one standard deviation gives rise to a 2-fold risk of spine fracture and a 2.5 fold risk of hip fracture. There is also data to support a higher rate of fracture in states of high bone turnover. If an intervention works to lower bone turnover, it should be associated with lower fracture risk. This may in part explain why a modest increase in bone density may be associated with a lower fracture rate. Needless to say, a fragility fracture, especially of the hip is associated with significant morbidity and mortality. Vertebral fractures are can be associated with severe pain and morbidity due to a postural effect on cardiopulmonary and gastrointestinal symptoms. Osteoporosis and its consequences can pose a significant psychological burden, on those affected. The goal is to prevent osteoporosis and the associated fragility fractures.

When to Refer

All physicians should be cognizant of patients with possible bone loss. In particular, family practitioners, internists, gynecologists, and Orthopaedists will be in optimal positions to assess for increased risk of fragility fractures in their patients. Any physician treating disorders that predispose to osteoporosis or any physician prescribing drugs that predispose patients to osteoporosis should be evaluating bone density. Physicians should refer patients to others specializing in metabolic bone disease if he/she is:

1. unfamiliar with the appropriate work-up if bone density is less than that expected for age-matched controls
2. unfamiliar with the various treatment options available for osteoporosis
3. unable to improve bone density and/or bone markers with seemingly appropriate therapy.