Osteoporosis

Suzanne L. Quinn, M.D.
Suzanne Quinn, M.D. is an Endocrinologist in
private practice at Methodist Medical Center.

Osteoporosis is the silent killer of modern medicine. It affects 75 million people around the western world and Japan¹ many of whom are unaware of the diagnosis until they suffer a life-altering fracture. As a result, the annual economic burden of osteoporosis in the United States alone was $20 billion in 1990 and is expected to reach $62 billion by the year 2020.² These numbers exceed the cost of congestive heart failure, asthma and breast cancer combined. Therefore, the goal of this paper is to convince the reader that the diagnosis, treatment and prevention of osteoporosis is a national health emergency.

Basics Of Bone Metabolism

Bone is a dynamic organ. As children grow bone is amassed. It continues to be structured and restructured as follows. Osteoclasts "digest" small canals in bone tissue. Osteoblasts follow along behind the osteoclasts and fill in the defects. In normal remodeling the amount of bone resorbed and laid down is neutral or in positive balance. Bone continues to accumulate to a peak bone density in the early thirties. After that there is a slow decline in bone mass until menopause at which time the bone loss accelerates (Figure 1). This is believed to occur because estrogen (and testosterone) are thought to prevent the resorptive effects of parathyroid hormone on bone.³

Figure 1. Bone Mass In Women

In order to be healthy, bone needs weight-bearing work. Decreasing exercise with age also contributes to cumulative bone loss. When bone becomes sufficiently "thin" or of poor quality fractures occur. Although there are many definitions for osteoporosis most of them attempt to describe bone mass as it relates to fracture risk.

Definition

In April 1993 the Consensus Development Conference defined osteoporosis as a "systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture."¹ The World Health Organization defines osteoporosis as a "bone mineral density less than 2.5 SD below mean peak value in young adults."² (Osteopenia is bone density which is less than normal but not 2.5 SD below normal bone density.) While this definition is less descriptive it is the one most often used by radiologists when they measure bone density and it gives the physician an idea of fracture risk.

Diagnosis

Osteoporosis can be diagnosed in a number of ways. A simple x-ray sometimes shows de-mineralized bone. However, osteopenia on a plain film usually implies a bone loss of 30% or more and as such is a very insensitive test. In the vertebral column loss of horizontal trabeculation, ballooning of discs and the classic anterior wedge fracture are commonly seen. Other diagnostic procedures include single or dual photon absorptiometry and quantitative CT scan. These tests are either imprecise or utilize large doses of radiation. Therefore, the most widely used diagnostic maneuver is dual energy x-ray absorptiometry or DEXA. DEXA is generally performed on at least two of three affected sites: wrist, spine and hip. The test is completed in minutes and involves so little radiation that the technologist requires no protection. In obtaining a DEXA, the bone density is reported as two "scores." The T score (Figure 2) is the bone density expressed as the number of standard deviations below the mean peak adult value. A T score of -2.5 SD or greater is osteoporosis by definition. The Z score (Figure 3) is the number of standard deviations below an age-matched control. The T score is used to make the diagnosis while the Z score (less than -2.0) is used as an indication of possible complicating factors in addition to menopausal osteoporosis. A T score lower than -2.5 requires treatment to prevent fractures and increase bone mass.⁴ A T score lower than -1.0 within five years after menopause indicates accelerated bone loss requiring prophylaxis against further loss.⁵ There are currently a number of portable densitometry machines available which can evaluate bone mass in the wrist or heel within minutes. Generally these results should be confirmed by measuring bone mass in the hip and spine with one of the standard instruments.

Figures 2 and 3. Interpreting Bone Mass Measurements Reports
Source: Compston JR, Cooper C and Kanis JA. Bone densitometry in clinical practice. Br Med J. 1995; 310: 1507-1510.

In addition to radiologic procedures, certain biochemical markers of bone turnover are sometimes followed as well because response to therapy can be seen in as little as six weeks compared to six to twelve months for bone density. There are no reliable serum markers of bone resorption, but several reliable urine markers can be useful. These involve a 24 hour urinary calcium excretion or the calcium to creatinine ratio and are most reliable when the patient is on a low calcium diet. (This may not however be practical.) A calcium to creatinine ratio > 0.15 in the second AM urine indicates endogenous loss of skeletal calcium. Hydroxyproline, a collagen breakdown product, can also be measured in a 24 hour urine collection or as a hydroxyproline to creatinine ratio (> 21mg/g) but since hydroxyproline is a component of many types of collagen it is less specific for skeletal loss. Markers of bone formation include serum osteocalcin, bone specific alkaline phosphatase or procollagen extension peptides. Unfortunately, since osteoporosis results from an upset in the balance between formation and resorption, it can occur in high or low bone turnover states making these tests rather complicated to interpret.

Screening For Osteoporosis

Obviously those patients at risk for osteoporosis are the ones who need to be screened. This includes all women aged 65 or older as well as postmenopausal women under 65 with one or more risk factors other than menopause.⁶ It may also be necessary to follow these women one year later to assess the rate of bone loss especially if hormone replacement does not occur. Other individuals with risk factors regardless of age, sex or reproductive status should also be evaluated although enough data for specific recommendations is still not available. Tables 1 and 2 respectively describe the general risk factors and medical risks factors for developing osteoporosis. Not all insurance carriers cover osteoporosis screening but a new diagnosis code (V82.81) for prevention/screening has been proposed. If accepted this code should become effective in October 1999. When screening is not covered by insurance, the arm span and height of the patient can be measured. Patients whose arm span is 2.0 to 2.5 cm greater than their height may be losing vertical height. Loss of vertical height confirms the diagnosis of osteoporosis and bone densitometry should be measured. All women with multiple risk factors who are over the age of 70 can be considered at high enough risk of fracture to begin treatment without bone mineral density (BMD) testing.⁶ Figure 4 illustrates a simple method for estimating daily calcium intake.

Treatment

All individuals need to maintain some degree of physical activity. A dietary calcium intake of 1200 - 1500 mg/day in addition to 400-800 IU per day of Vitamin D are recommended for all at-risk individuals. Elders with dairy product intolerance have difficulty achieving this degree of calcium ingestion without dietary consultation and/or calcium supplements.

FDA-Approved Drugs For Osteoporosis

Hormone replacement therapy (HRT) or estrogens have been shown to reduce vertebral fractures 50 to 80% and nonvertebral fractures by 25% with five years of use^7-9 and further reduction in fracture rate is anticipated with longer use. HRT has also been shown to have protective effects against heart disease, dementia and genitourinary problems. On the other hand, HRT may produce a slightly increased risk of breast cancer and endometrial cancer. Therefore, all women considering estrogen replacement for any of its benefits should receive counseling regarding its risk:benefit ratio.

Raloxifene is a mixed estrogen agonist-antagonist known as a selective estrogen receptor modulator (SREM). It has been shown to decrease bone resorption and increase bone mineral density by 2 to 2.5% in two years^10,11 as well as decreasing low density lipoprotein. This is less effective than conventional HRT and reductions in fracture rate still need confirmation. Raloxifene cannot be used to treat menopausal symptoms and it does not stimulate endometrial growth but it may provide an alternative to HRT for treatment of osteoporosis. Raloxifene is approved for prevention but not treatment of osteoporosis.

Alendronate is the most popular of the bisphosphonate derivatives. (Bisphosphonates are stable derivatives of the pyrophosphate moiety of bone structure.) It has been shown to increase bone density in the spine 7 to 10% and the hip 6% over three years resulting in 63% fewer vertebral fractures.¹² It must be taken on an empty stomach with a full eight ounces of water sitting upright for thirty minutes because of its limited GI absorption. A dose of 10 mg is recommended to treat osteoporosis while 5 mg has been approved by the FDA for prevention of bone loss. If an individual can tolerate the associated GI side effects, alendronate can be a powerful alternative or addition to HRT in the treatment of osteoporosis. Risedronate is a newer bisphosphonate that binds to hydroxyapatite. Doses of 2.5 and 5 mg have the same side effect profile as alendronate. In individuals treated with 5 mg for two years, BMD increased 5.7%.¹³ Risedronate and alendronate, are two compounds of the same class. Neither appears to have any particular advantage over the other. Currently, only alendronate has FDA approval for treatment of osteoporosis.

Calcitonin is a polypeptide hormone which can be given intranasally or less often by injection for the treatment of osteoporosis. The intranasal dose is 200 mcg. given once daily and may decrease the vertebral fracture rate by 40 to 50%.¹⁴ It acts to inhibit bone resorption and is felt to be safe although less effective than either HRT or alendronate. Calcitonin may have some added analgesic benefits which the other agents do not.¹⁵

Non-FDA Approved Drugs

Sodium fluoride stimulates new bone formation by unclear mechanisms but the quality of the new bone is questionable. In the Fluoride and Vertebral Osteoporosis Study,¹⁶ fluoride significantly increased bone mineral density but had no effect on fracture rate.

Calcitriol is a synthetic vitamin D analog which enhances calcium absorption from the GI tract. It is extremely useful in the treatment of hypocalcemia associated with renal disease or hypoparathyroidism but does not reduce the risk of fracture in osteoporosis alone.

Parathyroid hormone has been shown to increase BMD in the spine but not in the hip. No data is available yet on fracture rate. It appears to be most effective when used in combination with estrogen replacement.¹⁷

Summary

Osteoporosis represents a tremendous economic burden as well as a health risk. Much can be done to prevent osteoporosis through screening, early intervention and healthy life style modifications. The Osteoporosis National Foundation has published a guide to help physicians in this endeavor. Unfortunately, the effects of treatment on BMD progress slowly and therapies are considered successful if they only halve the fracture rate. A new fracture is not necessarily a treatment failure and continued therapy should be encouraged. Our ultimate goal is the elimination of osteoporosis.

REFERENCES

1. Who are candidates for prevention and treatment for osteoporosis? Osteoporos Int. 1997; 7:106.
2. Kanis KA. Osteoporosis and its consequences. Osteoporosis. Blackwell Science Ltd. p.18 (1993 Data).
3. Riggs BL, Melton LJ III. Involutional osteoporosis. N Engl J Med. 1996; 314:1676-1686.
4. Eddy DM, Johnston CC, Cummings SR, et al. Osteoporosis cost effectiveness analysis and review of the evidence for prevention, diagnosis and treatment: the basis for a guideline for the medical management of osteoporosis. Osteoporosis Int. (In press.)
5. Johnston CC Jr, Melton LJ III, Lindsay R, Eddy DM. Clinical indications for bone mass measurements. J Bone Miner Res. 1989; 4(Suppl 2):1-28.
6. Physician's Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation. 1998.
7. Kiel DP, Felson DJ, Anderson J, et al. Hip fracture and the use of estrogens in postmenopausal women: The Framingham Study. N Engl J Med. 1987;31:1169-1174.
8. Maxim P, Ettinger B, Spitalny GM. Fracture protection provided by long-term estrogen Treatment. Osteoporosis Int. 1995;5:23-29.
9. Paganini-Hill A, Ross RK, Gerkins VR, et al. Menopausal estrogen therapy and hip fractures. Ann Intern Med. 1981;95:28-31.
10. Draper MW, Flowers DE, Huster WJ, et al. A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res. 1996; 11:835-842.
11. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. N Engl J Med. 1997;337:1641-1647.
12. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995;333:1437-1443.
13. Mortensen L, Charles P, Bekker PJ, et al. Risedronate increases bone mass in an elderly postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab. 1998; 83:396-402.
14. Rico H, Revilla M, Hernandez ER, et al. Total and regional bone mineral content and fracture rate in postmenopausal osteoporosis treated with salmon calcitonin: a prospective study. Calcif Tissue Int. 1995; 56:1811-185.
15. Gennari C, Agnusdei D, Camporeale A. Use of calcitonin in the treatment of bone pain associated with osteoporosis. Calcif Tissue Int. 1991; 49(Suppl 2):S9-S13.
16. Meunier PJ, Sebert JL, Reginster JY, et al. Fluoride salts do not better prevent vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis. The Favos Study. Osteoporosis Int. (In press.)
17. Lindsay R, Nieves j, Formica C, et al. Randomized controlled study of effect of para-thyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on estrogen with osteoporosis. Lancet. 1997;350:550-555.

Jacksonville Medicine / January, 1999

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