The Diagnosis and Treatment of Primary Osteoporosis According to Current Guidelines

Introduction: Osteoporosis is the most common generalized disease of the skeleton, yet it is markedly undertreated in Germany.
Methods: Selective literature review on the basis of the current German guidelines regarding the prevention, diagnosis, and treatment of osteoporosis in postmenopausal women and in men aged 60 and above, and a further search of literature published in the last three years.
Results and discussion: The indication for dual X-ray absorptiometry (DXA) measurement for the specific diagnosis of osteoporosis is derived from the patient's age, sex, history of fractures in the past, and further risk factors. The therapeutic threshold for osteoporosis has been set at a 30% predicted risk of osteoporotic fractures occurring within 10 years. The treatment consists of basic measures for fracture prevention combined with specific pharmacotherapy. The recommended drugs for the treatment of osteoporosis in postmenopausal women in particular are alendronic and ibandronic acid, raloxifen, risedronic acid, and strontium ranelate; the only approved drugs for men at present are alendronic and risedronic acid and teriparatid. Intensive patient education markedly improves the otherwise poor compliance with osteoporosis treatment.
Dtsch Arztebl Int 2008; 105(33): 573–82
DOI: 10.3238/arztebl.2008.0573
Key words: osteoporosis, guidelines, diagnosis, therapeutic threshold, compliance

Osteoporosis, a generalized skeletal disease, is one of the most common illnesses of old age. More than 200 million persons suffer from it worldwide. Health-care statistics reveal that patients with this disease in Germany are often undertreated or incorrectly treated (1). The Association of German-Language Scientific Osteological Societies (Dachverband der deutschsprachigen wissenschaftlichen osteologischen Gesellschaften, DVO) has issued S3 guidelines on the prevention, diagnostic evaluation, and treatment of osteoporosis in postmenopausal women and in men aged 60 and over (2). These guidelines form the basis of this article. S3 guidelines are the highest class of German guidelines. They are based on a systematic analysis of the available scientific evidence and produced by a representative panel of experts and are issued after a structured process of consensus building.

The learning objectives of this article are as follows: after reading it, the reader should be able to

- recognize the clinical abnormalities and risk factors that suggest the possible development of osteoporosis,
- apply the correct indications for the diagnostic evaluation of osteoporosis according to the DVO guidelines,
- know the basic practical steps involved in fracture prevention and in the specific pharmacotherapy of osteoporosis.

The literature consulted for this article included not just the publications found in a systematic search of the literature up to January 2005 that was performed for the 2006 DVO guidelines, but also further publications revealed by a PubMed search on 25 November 2007 on the items "osteoporosis," "fracture," and "treatment." The latter search was restricted to randomized controlled trials, meta-analyses, and guidelines. The authors also performed a manual search of relevant German-language primary care journals. In this article, individual publications are cited only if they were not mentioned in the DVO guidelines. The reader is also referred to the DVO guidelines for further information on levels of evidence and strengths of recommendations; the executive summary and the pocket version of the guidelines are particularly useful for this purpose (see www.lutherhaus.de/dvo-leitlinien).

Definition and epidemiology
Several definitions of osteoporosis have been proposed. The most commonly accepted at present is the one proposed in 2001 by the National Institutes of Health Consensus Development Panel on Osteoporosis, in which the risk of fracture plays a central role. According to this definition, osteoporosis is a systemic skeletal disease characterized by low bone mass and impaired microarchitecture of bony tissue, as a result of which the bones are more fragile than normal.

Among women aged 50 to 79, the annual incidence of morphometrically demonstrable vertebral body fractures is 1%, and that of peripheral fractures is 1.9%. The corresponding figures in men are 0.6% and 0.7%. The fracture rate rises exponentially with age (figure 1 gif ppt). While the overwhelming majority of vertebral body fractures are due to osteoporosis, peripheral fractures are due to a variable combination of endogenous and exogenous factors depending on their location and on the mechanism of the precipitating injury. In each individual case, the physician must determine whether the fracture should be considered osteoporotic or traumatic. An osteoporotic fracture should be suspected when a fracture has resulted from a fall from the standing position or from a low height. It is also true, however, that patients sustaining peripheral fractures as a result of traumatic forces that ordinarily suffice to cause such fractures tend to have lower than normal bone density (3). Thus, even in cases of this kind, the physician must decide whether to perform a further diagnostic evaluation for osteoporosis.

Clinical features
Osteoporosis without fractures is an asymptomatic condition. Osteoporosis that becomes symptomatic by causing one or more fractures is called manifest osteoporosis. X-rays then reveal typical vertebral body deformities, such as wedge vertebrae or biconcave ("fish") vertebrae. Osteoporotic fractures and deformities can cause severe acute and chronic pain. Vertebral body fracture is the most common type of osteoporotic fracture, while proximal femoral fracture is the type with the most serious sequelae (4).

Patients with osteoporotic fractures have an increased rate of mortality, particularly in the first year after the fracture event, and a high risk of further fractures. The body habitus of patients with osteoporosis is characterized by progressive kyphosis of the thoracic spine ("dowager's hump") and the loss of at least 4 cm of height, sometimes as much as 10 cm or more (figure 2 jpg ppt). Shortening of the trunk can bring the lower rib cage into painful contact with the iliac crest; the abdomen protrudes ("osteoporosis belly"), and the limbs seem to be excessively long in relation to the trunk. Typical skin folds appear that run down the back laterally to the flanks. This is commonly referred to as the Tannenbaum-Phänomen („fir tree phenomenon“), as the folds of skin appear to 'hang' from the spine, thereby resembling the branches and trunk of a fir tree (figure 3 jpg ppt). The body's center of gravity is displaced forward. The patient's gait becomes small-stepped and unsteady.

Risk factors
A number of different biological factors that promote fractures need to be taken into consideration: not just bone density, but also the patient's age and sex, any previous fractures typical of osteoporosis, and any other independent risk factors for such fractures (box 1 gif ppt). When all of these things are considered, the individual patient's risk of fracture can be evaluated much more reliably than with bone densitometry alone, and the expected effects of treatment can be calculated more precisely.

Indications for diagnostic evaluation
The DVO guidelines set the threshold for initiating a diagnostic evaluation for osteoporosis at a 20% 10-year risk of sustaining a fracture that is typical for osteoporosis. This probability is assessed solely on the basis of the patient's history and physical findings. If the threshold is exceeded, a specific diagnostic evaluation is recommended (table 1 gif ppt).

The specific fracture risk in men is only half of the risk in women of the same age. Consequently, men reach any given level of risk 10 years later than women do.

In addition to age and sex, a previous vertebral body fracture markedly increases the risk of further fractures in the vertebral bodies or elsewhere; peripheral fractures, on the other hand, confer a variably severe risk of further fractures, depending on their localization and the mechanism of injury that produced them. Therefore, when a peripheral fracture occurs, it should be assessed in each individual case whether this particular fracture arouses a high degree of suspicion for osteoporosis. If so, and if the patient is a woman aged 50 or older or a man aged 60 or older, then further diagnostic evaluation is indicated. The treating physician should also initiate a specific diagnostic evaluation for osteoporosis in a woman aged 60 or older, or a man aged 70 or older, if one or more of the risk factors listed in box 1 is present and cannot be eliminated by treatment. Finally, all women aged 70 or older and all men aged 80 or older should undergo a specific diagnostic evaluation for osteoporosis, as long as a positive finding would carry therapeutic implications for the individual patient.

The specific diagnostic evaluation for osteoporosis involves the performance of bone densitometry. Dual X-ray absorptiometry (DXA) is the preferred method for this, because all of the large therapeutic studies to date have been based on it. DXA values should be measured in the lumbar spine (vertebrae L1 through L4) and in the proximal femur; the lower of the two values should be used for further calculations. The "T value" is a derived parameter representing the difference between the patient's bone density and the average value in a population of normal 30-year-old people, expressed in standard deviations from the mean. Thus, a T value of –1, for example, signifies that the patient's bone density is one standard deviation below the mean. When the T value is less –2, the patient's bone density is lower than that of 95% of the normal middle-aged population. Any person with a T value below –1 is said to have osteopenia, while any person with a T value below –2.5 is said to have osteoporosis. The measured T value, however, does not itself constitute an indication for treatment. Statutory health insurance in Germany will reimburse bone densitometry only if there has also been a fracture that is suspect for osteoporosis.

Bone density is relatively stable among persons over age 60 in the absence of other factors such as severe vitamin D deficiency, prolonged immobility, and systemic glucocorticoid treatment. Thus, repeated measurements should only be performed for special indications (5). Because bone density, age, sex, and prior osteoporotic fractures are independent risk factors for future fractures, the combination of these data allows a much more accurate estimation of the risk. Prediction becomes even more accurate, though substantially more complicated, when further risk factors are included in the model. Further risk factors do not cumulate without limit, however; they lead, at most, to a doubling of the risk in the model that was used.

Table 2 (gif ppt) shows how the threshold for treatment is derived from the T value, age, and sex of the patient. The DVO guidelines recommend specific treatment when the 10-year risk of osteoporotic fractures exceeds 30%.

This level of risk is already reached in persons over age 50 with a vertebral body fracture typical of osteoporosis when the T value is below –2.0.

Further risk factors that can be included in the model are listed in tables 1 and 2. They elevate the risk of fracture by a factor of 1.5 to 2. Thus, for simplicity, if one or more of these factors is present, then the threshold T value for treatment is obtained by considering the patient to be one decade older (i.e., moving two rows down) in table 2. There is no specific therapeutic recommendation if the patient is irreversibly bedridden.

Basic diagnostic evaluation
If the patient has sustained a fracture that arouses the suspicion of osteoporosis, but the bone density is not abnormally low, then the following basic diagnostic evaluation should be performed to detect any of the possible causes of secondary osteoporosis and any modifiable risk factors for further fractures, as well as to provide a baseline for further clinical observation.

- The patient should be asked about any musculoskeletal pain, functional limitations, previous falls, dietary habits, and physical activity, including exposure to sunlight.
- The patient should also be asked about the use of any medications that tend to promote osteoporosis or that increase the likelihood of falling, particularly antiepileptic drugs (e.g., carbamazepine), antidepressants (particularly tricyclic agents), other drugs causing sedation or orthostatic hypertension, and oral glucocorticoids.
- The risk of falling should be assessed, e.g., with a timed up-and-go test or a chair-rising test, perhaps as part of a more extensive geriatric assessment (box 2 gif ppt).
- The patient's height and weight should be measured so that the body-mass index (BMI) can be calculated.
- X-rays should be performed to detect vertebral body fractures if there is any suggestive clinical evidence such as a history of sudden, severe back pain or a loss of more than 4 cm of height, and as long as the detection of such fractures would have clinical consequences.
- Basic osteological laboratory parameters should be measured (table 3 gif ppt).

Treatment
The treatment of osteoporosis is divided into basic measures for fracture prevention and the specific pharmacotherapy.

Basic measures for fracture prevention
The first step consists of intensive counseling about living habits that promote bone health. These lifestyle factors should, in principle, be recommended to all patients, even those who have not undergone a specific diagnostic assessment for osteoporosis:

- Avoidance of underweight (the BMI should not fall below 20)
- Smoking cessation
- Adequate calcium intake (1200 to 1500 mg daily)
- Regular physical exercise with adequate weight-bearing to promote strength and coordination, e.g., hiking, dancing, gymnastics, weight training
- An average of 30 minutes of sunlight exposure per day, with uncovered head and hands, to prevent vitamin D deficiency
- Review of the need for, and the doses of, any of the medications mentioned above that promote osteoporosis and increase the likelihood of falling.

Directed exercise programs can, at least, reduce the risk of falling, although the studies performed to date have included too few patients to demonstrate any resulting reduction of the fracture rate (2, 6). Because fractures are relatively rare events, very large studies would be needed to demonstrate this. Thus, the authors can only point to indirect evidence from epidemiological studies showing that more frequent falls (i.e., two or more falls in the past six months) increase the fracture rate. It is reasonable to conclude, therefore, that the fracture rate will be lower if falls are prevented.

It is often difficult to put the recommended basic measures into consistent practice; this is just as true in nursing homes as it is elsewhere (7). Thiazide diuretics promote calcium retention and therefore presumably have a synergistic effect with the basic measures when they are given to treat high blood pressure or for other indications.

Calcium and vitamin D supplementation is a standard recommended element of the specific pharmacotherapy of osteoporosis. The vitamin D dose should be 400 to 1200 IU per day, depending on the presumed severity of the vitamin D deficit. Vitamin D can also be given in higher doses (boluses) at longer intervals.

The daily supplementation of at least 1200 mg of calcium in combination with 800 IU of vitamin D is recommended on the basis of a recent meta-analysis (8).

There are conflicting data on the possible benefit of hip protectors. They are most likely to protect patients in nursing homes if they are worn consistently.

Specific pharmacotherapy
When the 10-year risk of fractures exceeds 30%, specific pharmacotherapy is clearly indicated because the benefit considerably outweighs the risk. The DVO guidelines recommend the following medications (in alphabetical order) for post-menopausal women with a specific indication for treatment: alendronate, ibandronate, raloxifene, risedronate, and strontium ranelate. Estrogens prevent fractures just as effectively, but, because of their risks, they should no longer be used as primary treatment for osteoporosis, except when they are indicated to treat other conditions as well, such as severe hot flashes. Teriparatide (parathormone fragment 1–34) is only approved for the treatment of manifest osteoporosis over an 18-month period.

When the DVO guidelines were published, only alendronate had been approved for the treatment of osteoporosis in men. In the meantime, risedronate, and teriparatide have been approved as well. Also since the publication of the guidelines, therapeutic studies with positive results in postmenopausal osteoporosis have appeared, and two new drugs have been approved: zoledronate administered intravenously once per year (9) and intact parathormone (10).

Oral biphosphonates have relatively few adverse effects. These include gastrointestinal disturbances (usually esophageal irritation) and myalgia, particularly around the start of treatment. High-dose parenteral bisphosphonate treatment for patients with tumors has been found to elevate the rate of osteonecrosis of the jaws, but no such elevation has been found when the drug is used for osteoporosis (11).

All of these drugs lower the frequency of morphological and symptomatic vertebral body fractures by about half, and that of peripheral fractures by about one-third. When the 10-year risk of fractures is 30% or higher, the absolute risk reduction is at least 10% to 15%, and the number needed to treat (NNT) is thus below 100 for one year, or below 10 for 10 years (2). This effect is markedly stronger than the indication thresholds that are generally set, e.g., in cardiovascular medicine.

In addition, patients with manifest osteoporosis should have adequate pain control and rehabilitative measures.

The optimal moment for the performance of a vertebroplasty or kyphoplasty in patients with osteoporotic vertebral body fractures is currently debated (12). The DVO guidelines recommend vertebroplasty or kyphoplasty only after an unsuccessful three-month trial of multimodal conservative treatment (2).

Patient education
The patient's ability to tolerate the treatment and, in particular, to comply with it should be checked three to six months after its initiation, and thereafter at yearly intervals. Patients tend to comply only moderately well with calcium and vitamin D supplementation and with the specific pharmacotherapy of osteoporosis (13, 14).

Compliance can be improved by intensive education of osteoporosis patients as soon as the diagnosis is made. Among a group of patients who went through the "Nümbrecht osteoporosis school," a standardized and evaluated multimodal osteoporosis education program consisting of nine modules, 72% were still taking their osteoporosis medications six months later, and 62% were still taking them at 1 year. There was, however, no control group of patients that did not undergo patient education (15, 16).

Duration of pharmacotherapy for osteoporosis
Bone densitometry should generally be repeated no sooner than two years after the initiation of treatment. It should be performed, in particular, when there is reasonable doubt as to the indication for, or particular choice of, treatment, or when the discontinuation or restarting of pharmacotherapy is being considered.

Medications for osteoporosis should be given for three to five years at first. The patient should then be re-evaluated.

When bisphosphonates are discontinued, their osteoprotective effect declines very slowly, because they remain bound in bone.

In a five-year follow-up study, a group of patients in whom bisphosphonate therapy was continued did better than a control group only with respect to densitometric values and clinically manifest vertebral body fractures. The overall fracture rates were the same.

Thus, the continuation of specific pharmacotherapy is justified in patients who have a relatively long residual life expectancy and whose fracture risk is still high. In other patients, the medications can be discontinued and the further course can be observed (17).

Summary
The indications for the diagnostic evaluation of osteoporosis and for its treatment are based on the risk of fracture. Unlike arteriosclerosis, which is a progressive process, bone is continuously being laid down and resorbed throughout the life of the patient. It is, therefore, not an effective means of fracture prevention to initiate maximal treatment in a 50-year-old patient, in order to reduce a risk that will become manifest more than 20 years later. The medical treatment of osteoporosis exerts its effects relatively rapidly: numerous studies have demonstrated significant changes after as little as six to twelve months. If a fracture has already occurred, however, it is important to intervene rapidly to prevent further fractures and the resulting severe functional limitations. Too little is being done in this area in Germany at present.

A variety of interventions involving changes in physicians' and patients’ behavior, new computer systems, and improved access to DXA measurements can bring about improvements in the specific diagnostic evaluation of osteoporosis and thereby partly lower fracture rates (18–23). All physicians caring for elderly patients with fractures bear the responsibility of diagnosing and treating osteoporosis adequately. Both screening (i.e., the examination of all probands in a particular age group) and case-finding (i.e., the directed diagnostic evaluation of patients at elevated individual risk) for osteoporosis are cost-effective even in the absence of a previous fracture typical of the disorder and can reduce the frequency of severe functional impairment (25). Unfortunately, however, screening and case-finding are not yet covered by statutory health insurance in Germany. The affected patients should be informed of this if they would be motivated to undergo treatment in the event of a positive diagnosis.

Conflict of interest statement
Professor Peters has received financial reimbursement for lecturing activities from the Procter & Gamble, Novartis, Lilly Deutschland, and Servier Deutschland companies. Professor Baum declares that she has no conflict of interest as defined by the International Committee of Medical Journal Editors.

Manuscript received on 18 April 2008; revised version accepted on
12 June 2008.

Translated from the original German by Ethan Taub, M.D.


Corresponding authors
Prof. Dr. med. Klaus M. Peters
Rhein-Sieg-Klinik
Höhenstr. 30
51588 Nümbrecht, Germany
[e-mail]

References

1. Häussler B, Grote H, Mangiapane S, Glaeske G, Pientka L, Felsenberg D: Versorgung von Osteoporose-Patienten in Deutschland. Dtsch Arztebl 2006; 103(39): A 2542–8.

2. Dachverband der deutschsprachigen wissenschaftlichen osteologischen Gesellschaften für Osteologie (DVO) e.V.: Osteoporose-Leitlinie. Langfassung. Stuttgart, New York: Schattauer 2006.

3. Mackey DC, Lui LY, Cawthorn PM et al.: High-trauma fractures and low bone mineral density in older women and men. JAMA 2007; 298: 2381–8.

4. Peters KM: Osteoporose. In: Bischoff HP, Heisel J, Locher H (Hrsg.): Praxis der konservativen Orthopädie. Stuttgart, New York: Thieme 2007; 468–77.

5. Hillier TA, Stone KL, Bauer DC et al.: Evaluating the value of repeated bone mineral density measurement and prediction of fractures in older women. Arch Intern Med 2007; 167: 155–60.

6. Harada A: Exercise for fall prevention and osteoporosis treatment. Nippon Rinso 2006; 64: 1687–91.

7. Cólon-Emeric CS, Lyles KW, House P et al.: Randomized to improve fracture prevention in nursing home residents. Am J Med 2007; 120: 886–92.

8. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A: Use of calcium or calcium in combination with Vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370: 657–66.

9. Geusens PP, Lems WF: Fracture prevention in postmenopausal women with osteoporosis by annual infusion of zoledronic acid. Ned Tijdschr Geneeskd 2007; 151: 1445–8.

10. Vestergard P, Jorgenson NR, Mosekilde L, Schwarz P: Effects of parathyroid hormone alone or in combination with antiresorptive therapy on bone mineral density and fracture risk – a meta analysis. Osteoporos Int 2007; 18: 45–57.

11. Jefcoat MK: Safety of oral bisphosphonates: controlled studies on alveolar bone. Int J Oral Maxillofac Implants 2006; 21: 349–53.

12. Haas H, Amling M, Baier M et al.: Zur Anwendung der Ballon-Kyphoplastie/Vertebroplastie. Osteologie 2008; 17: 11–6.

13. Prince RL, Devine A, Dhaliwal SS, Dick IM: Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006; 166: 869–75.

14. Segal E, Tamir A, Ish-Shalom S: Compliance of osteoporotic patients with different treatment regimens. IMAJ 2003; 5: 859–62.

15. Peters KM, Hasselberg J, Bode M: Compliance der medikamentösen Osteoporosetherapie nach Teilnahme am Osteoporoseschulungsprogramm. Osteologie 2007; 16: 30–1.

16. Peters KM, Bode M: Nümbrechter Osteoporose Schule. Steinkopff 2008.

17. Black DM, Schwartz AV, Ensrud KE et al.: Effects of continuing or stopping Alendronate after 5 years of treatment. JAMA 2006; 296: 2927–38.

18. Gardner MJ, Brophy RH, Demetrakopoulos D: Interventions to improve treatment following hip fracture: a prospective, randomized trial. J Bone Joint Surg Am 2005; 87: 3–7.

19. Morrison LS, Tobias JH: Effect of case-finding strategy for osteoporosis on bisphosphonate prescribing in primary care. Osteoporos Int 2005; 16: 71–7

20. Lacroix AZ, Buist DS, Brennemann SK, Abbott TA: Evluation of three population-based strategies for fracture prevention: results of the osteoporosis population-based risk assessment (OPRA) trial. Med Care 2005; 43: 293–302.

21. Feldstein A, Elmer PJ, Smith DH et al.: Electronic medical record reminder improves osteoporosis management after a fracture: a randomized, controlled trial. J Am Geriatr Soc 2006; 54: 606–7.

22. Bliuc D, Eisman JA, Center JR: A randomized study of two different information-based interventions on the management of osteoporosis in minimal and moderate trauma fractures. Osteoporos Int 2006; 17: 1309–17.

23. Solomon DH, Polinski JM, Stedman M et al.: Improving care of patients at risk for osteoporosis: a randomized controlled trial. J Gen Intern Med 2007; 22: 362–7.

24. Schousboe JT, Ensrud KE, Nyman JA, Melton LJ, Kane RL: Universal bone densitometry screening combined with alendronate therapy for those diagnosed with osteoporosis is highly costeffective for elderly women. J Am Geriatr Soc 2005; 53: 1697–704.