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Osteoporosis and bone
The diagnosis of osteoporosis requires an found to affect bone quality as well as its assessment of risk factors, the documenta- mineral density. Turner notes that anabolic tion of fractures, an evaluation of potential (PTH; also known as teriparatide), increase bone turnover and porosity, which can off- a direct relationship between bone density strength. Antiresorptive therapies reduce bone turnover, causing increased bone min- eralization, which can increase brittleness.6 However, recent studies, both animal andhuman, suggest that the preservation or However, there is a growing awareness that a reduction in bone mineral density is not accounts for an important part of the ben- the sole pathology underlying osteoporosis, efits of several current osteoporosis medica- nor do increases in BMD completely explain tions. In a study by Borah et al, the effects of successful therapy. Patients with similar risedronate on bone mass and architecture were evaluated in ovariectomized minipigs.
Approved for 1 hour of continuing medical fracture risks; and agents with differing months with either vehicle or risedronate at reductions in fracture risk.3 The missing doses of 0.5 mg/kg/day or 2.5 mg/kg/day.
factor appears to be bone quality. Legrand the quality of trabecular bone and vertebral was higher in both treated groups (p<0.05), Professor of Clinical Obstetrics and Gynecology University of Cincinnati College of Medicine osteoporosis.4 There were no significant dif- significant at the 2.5 mg/kg/day dose. At Director, University Hospital Menopause and ferences in BMD in patients with or without the higher dose of risedronate, trabecular fractures. However, patients with at least one thickness, trabecular number, and connec- vertebral fracture had significant alterations tivity were higher and trabecular separation with vehicle (p<0.05). Both normalized study suggests that altered trabecular bone architecture is a major determinant of osteo- Schnitzler adds higher mineralization and normalized stiffness of vertebral cores were less fatigue damage (which is influenced by pared with the vehicle group (p<0.05).
eralization, changes in cortical porosity, and Vertebral bone volume alone accounted for the health of osteocytes may also play roles in 76% of the variability in bone strength, while the quality of bone.3 Bone quality, as well as quantity, declines with age. The trabecular be involved; the most important is probably network becomes progressively disconnected and weaker. Old osteocytes die, leading to hypermineralization and brittleness. Bone collagen becomes unstable and unremodeled better connected.3 To these characteristics, bone acquires accumulated fatigue damage.5 Medical College of Virginia (VCU campus), activity evaluation questionnaire will be is accredited by the Accreditation Council claim only those hours of credit that he/she actually spent in the educational activity.
This educational activity was planned inaccordance with Accreditation Council for To earn 1 hour of category 1 credit, read the material in this newsletter carefully.
answer the post-test questions on theaccompanying questionnaire. Send the questionnaire in the enclosed envelope to: at risk for osteoporosis or with established Your credit certificate will be returned.
completing the post-test, the participant unrestricted educational grant fromMerck & Co., Inc.
■ Describe the effects of the discontinu- ation of estrogen on bone density andbone markers.
adopting a more aggressive approachto the diagnosis of osteoporosis.
Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Proctor & Gamble, Wyeth-Ayerst, Aventis, The educational information is presentedin an 8-page newsletter.
In a three-year trial, biochemical and histo- restore bone architecture by filling in cav- logical studies assessed bone quality and ities and cancellous bone. The effects of tained in men and significantly increased in quality differ with duration of treatment. A years or 20 mg/day for two years, followed study of short-term PTH use (56 days) was porosity. There was also an increase in tra- by 5 mg/day for one year.7 All patients also conducted in 2-year-old male rats treated becular connectivity density in the majority received 500 mg/day of calcium carbonate.
with daily injections of 15 nmol/kg PTH or of patients. The investigators concluded that vehicle.10 Rats treated with PTH showed a daily PTH has an anabolic effect on cortical from 231 patients from Phase III alendro- substantial increase in the strength of the bone in patients with osteoporosis and also nate studies at the end of either 24 or 36 vertebral body compared with those treated months of continuous treatment. In patients receiving active treatment, decreased bone cal analysis showed that compressive bone Arzoxifene, a new selective estrogen-recep- tor modulator (SERM), has also been shown turnover was achieved after six months of to maintain bone quality as well as BMD.
qualitative abnormalities. The investigators old ovariectomized rats and compared with found that alendronate did not impair bone controls.13 Both doses of arzoxifene pre- Another animal study suggested that long- eterious effects on bone quality.11 Young female rats received near-lifetime treatment with recombinant PTH at doses of 5, 30, or three-point bending testing of the femoral In a similar three-year trial, the effects of 75 µg/kg/day or vehicle controls for up to oral risedronate 5 mg/day on bone quality two years as part of an oncogenicity evalu- toughness were higher for treated animals.
was observed for all treatment groups.
Fluoride may also have beneficial effects on Transiliac bone biopsies were obtained at bone quality.14 When prescribed for the pre- vention of osteoporosis, fluoride modifies samples showed no undesirable qualitative duration, resulting in abnormal bone archi- the microscopic structure and biomechanical properties of bone. It stimulates bone for- becular fibrosis, or woven bone, associated mation, leading to trabecular hypertrophy absence of distinction between trabecular and cortical bone, and the femoral midshaft The effects of alendronate on bone quality when the concentration of fluoride in bone and turnover were also studied in secondary brittleness. The investigators concluded that becomes excessive, it can lead to mineraliza- PTH skeletal effects are a complex function tion defects; these weaken the bone despite of dose and duration and that, in rats, short- an increase in mass. Thus the benefits of had long-term glucocorticoid exposure. Pa- term treatment (six months or less) is more fluoride in preventing vertebral fractures are tients were randomized to receive placebo advantageous than near-lifetime treatment.
increases in trabecular bone mass and altera- for one year. Transiliac bone biopsies were Dempster et al examined the effect of daily then obtained for quantitative and qualitative analysis of bone. In addition to the antici- microarchitecture and turn-over in patients pated decrease in bone turnover, the inves- with osteoporosis.12 They obtained paired tigators found that alendronate treatment clinical techniques for measuring patients with osteoporosis before and after treatment with daily injections of 400 U of between the placebo and alendronate groups recombinant PTH. The first group of eight in trabecular bone volume or parameters of men was treated with PTH for 18 months.
desirable to develop scales for measuring hormone replacement therapy for the dura- selecting appropriate osteoporosis therapy, tion of the trial. Results showed that can- and assessing the results of treatment.3,15-17 REFERENCES 1. Bouxsein ML, Courtney AC, Hayes WC. Ultrasound and densitometry of the calcaneus correlate with the failure loads of cadaveric femurs. Calcif Tissue Int.
1995;56:99-103.
2. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. Br Med J. 1996;312:1524-1529. 3. Watts NB. Bone quality: getting closer to a definition. J Bone Miner Res. 2002;17(7):1148-1150.
4. Legrand E, Chappard D, Pascaretti C, et al. Trabecular bone architecture and male osteoporosis. Morphologie.
1999;83(261):35-40.
5. Schnitzler CM. Bone quality: a determinant for certain risk factors for bone fragility. Calcif Tissue Int. 6. Turner CH. Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporosis Int.
2002;13(2):97-104.
7. Meunier PJ, Arlot M, Chavassieux P, et al. The effects of alendronate on bone turnover and bone quality. Int J Clin Pract. 1999;101:14-17.
8. Eriksen EF, Melsen F, Sod E. Effects of long-term practical, noninvasive techniques for asses- risedronate on bone quality and bone turnover in womenwith postmenopausal osteoporosis. Bone. 2002;31(5): sing bone quality. Although there are several 9. Chavassieux PM, Arlot ME, Roux JP, et al. Effects quality of resected bone, such as multiple of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometricanalysis of transiliac biopsies. J Bone Miner Res. assessing bone microarchitecture have not yet been perfected.3 In a study published in 10. Ejersted C, Andreassen TT, Hauge EM, et al. Parathyroid hormone (1-34) increases vertebral bone mass, compres-sive strength, and quality in old rats. Bone. 1996;17(6): filter and pipeline analysis applied to com- 11. Sato M, Vahle J, Schmidt A, et al. Abnormal bone puted radiography (CR).18 On the basis of architecture and biomechanical properties with near- trabecular thickness, they divided observed lifetime treatment of rats with PTH. Endocrinology.
2002;143(9): 3230-3242. trabecular patterns into eight subsets. They 12. Dempster DW, Cosman F, Kurland ES, et al. Effects of subsequently developed criteria relating the treatment with parathyoid hormone on bone microarchi- tecture and turnover in patients with osteoporosis: strength of the bone. They were then able a paired biopsy study. Bone Miner Res. 2001;16(10):1846-1853. 13. Ma YL, Bryant HU, Zeng Q, et al. Long-term dosing of arzoxifene lowers cholesterol, reduces bone turnover, strength. By contrast, BMD alone correlated and preserves bone quality in ovariectomized rats. J Bone Miner Res. 2002;17(12):2256-2264. 14. Marcelli C, Meunier PJ. Fluoride therapy. Influence on the microarchitecture and biomechanical properties of bone. Presse Med. 1994;23(29):1344-1388.
porosis as a disease of low bone mass has 15. Wendlova J. Bone density and its quality. Bratisl Lek Listy. 2000;101:110-111.
16. Matsubara M, Morita S, Shinomiya K, et al. Structuring parameters for assessment of bone quality using a morphological filter and star volume analysis: structuring property in the cancellous bone of the human femoralhead. J Bone Miner Res. 2003;21(1):48-56.
osteoporosis as a disease characterized by 17. Capuani S, Alessandri FM, Bifone A, et al. Multiple spin echoes for the evaluation of trabecular bone quality.
deterioration.” 20 Current techniques for assessing microarchitectural deterioration 18. Matsubara M, Nakamura K, Morita S, et al. Non-invasive assessment of bone quality. J Med Dent Sci. 1999;46(4): are limited by their invasiveness. In the future, the diagnosis of osteoporosis will 19. Chesnut CH 3rd, Rose CJ; Bone Quality Discussion Group.
probably involve more accurate assessments Reconsidering the effects of antiresorptive therapies in of bone strength using noninvasive methods reducing osteoporotic fracture. J Bone Miner Res.
2001;16(12):2163-2172. 20. Consensus Development Conference. Prophylaxis and treatment of osteoporosis. Am J Med. 1991;90:107-110.
Preliminary EFFECT results:
Osteoporosis continues
NOF recommends
once-weekly alendronate
to be underdiagnosed ––
more aggressive approach to
superior to raloxifene for spine
even in patients with
diagnosis and treatment of
and hip BMD
fractures
Preliminary results of a year-long study of Despite advances in diagnostic technology, disease. In a recent retrospective cohort greater increases in bone mineral density study of 206 patients (146 female, 60 male) ment of Osteoporosis to reflect new treatment diagnosis and treatment of patients at risk diagnosed with osteoporosis.1 Furthermore, for fractures.1 Perhaps the most significant of Obstetricians and Gynecologists (ACOG).
men) received prescription medications for osteoporosis. Many of the patients had sev- eral risk fractures for osteoporosis, including risk factors. (The previous recommendation was to treat if T-scores were below -2.5.) who had multiple compression fractures of fene (n=233). Patients also received calci- treatment if T-scores are below -1.5 if one um 500 mg and vitamin D 400 IU daily.
or more risk factors are present (Table 1).
had osteoporosis, as defined by a T-score prevention is, in part, a response to the long- 0.98)were less likely to have been diagnosed awaited results of the National Osteoporosis with osteoporosis. Women with a prior hip Risk Assessment (NORA) trial, the largest spine T-score was -2.50. A history of frac- Bone mineral density was measured at base- have been diagnosed with osteoporosis.
line, at six months, and at 12 months. For the primary endpoint of percent change in The authors concluded that, in the primary BMD at the lumbar spine at one year, there care setting, physicians frequently did not diagnose osteoporosis in patients with verte- previously diagnosed with osteoporosis. The bral fractures, thereby missing an opportu- with those receiving raloxifene (4.4% vs.
nity to prevent future fractures in patients 1.9%, respectively; p<0.001). Similarly, total at high risk. They called for targeted efforts to improve diagnosis as an important step of heel, finger, or forearm, and clinical frac- ture rates at the 12-month follow-up.
loxifene at one year (p<0.001). In addition, porosis among women enrolled in the study the raloxifene arm (p<0.001). The response was surprisingly high. Based on the criteria rate, defined as the number of patients who testing for all women aged 65 and for post- for alendronate and 75% for raloxifene.
one or more additional risk factors.
osteoporosis (T- scores ≤ -2.5). Follow- 1. Neuner JM, Zimmer JK, Hamel MB. Diagnosis and treat- ment of osteoporosis in patients with vertebral compression fractures. J Am Geriatr Soc. 2003;51(4):483-491.
Table 1. Risk factors for osteoporotic fracture1
mary care practices have clinically significant ■ Personal history of fracture as an adult penia, there was a 1.8-fold increase in frac- increased risk of incident fracture within ■ History of fragility fracture in a first one year.”4 Given the personal, economic, and social impact of osteoporotic fractures, a more aggressive approach to diagnosis and ■ Low body weight (< about 127 pounds) can and should be done to identify and treat patients at risk for osteoporotic fractures.
■ Use of corticosteroid therapy for more Almost half of the patients enrolled in this study had previously undetected low BMDs.
1. Pocket Guide to Prevention and Treatment of Osteoporosis. Washington, D.C.: National OsteoporosisFoundation, 2003. that patients with T-scores of -1 to -2.49, 2. Siris E, Miller P, Barrett-Connor E, et al. Design of NORA, the National Osteoporosis Risk Assessment Program.
under previous NOF guidelines, had a frac- Osteoporosis Int. 1998;8(Suppl 1):S62-S69. ture risk almost double that of patients with 3. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: Chesnut notes that “. . NORA confirms what results from the National Osteoporosis Risk many clinicians and osteoporosis researchers Assessment. JAMA. 2001;286:2815-2822. have long suspected, i.e., that a significant 4. Chesnut CH. Osteoporosis, an underdiagnosed disease.
■ Alcohol intake in excess of 2 drinks per day JAMA. 2001; 286(22):2865-2866.
ABSTRACT
OBJECTIVE
as needed, and issuance of a prescription. All was presented at the ACOG 51st Annual Clinical Meeting, April 26-30, 2003, is low, similar to therapy for other chronic disorders. The purpose was to investigate the impact of an intensive counseling ses-sion by a specially trained nurse on therapy compliance, satisfaction, and therapy costs IC patients had higher rates of bone protec- tive drug use (79% versus 65%), satisfaction with care experience (8.4% versus 8.1%),and drug assistance program enrollment thresholds (National Osteoporosis Founda- and health plan drug acquisition costs per tion and/or high risk for hip fracture) were patient ($191 versus $215) than UC patients.
offered participation. They were randomized3:1 between the intensive counseling (IC) CONCLUSION
Structured counseling after DXA by a spe- patients). Patients in both groups received along with a 24-page pamphlet. Usual Care patients were instructed to contact theirordering provider to review results and dis-cuss therapy. Intensively Counseled patientsreceived concurrent counseling by a nurseincluding: indications, therapy advised,risks and/or side effects, costs, enrollmentin manufacturer’s drug assistance program CASE STUDY 1
The patient’s long-standing irritable bowel Her physical exam results showed a height of 5’5” (no loss), a weight of 150 lbs, and major proportion of IBS patients have gluten sensitivity. Celiac disease is an inherited noted. Her lab test results showed the fol- disorder caused by intolerance to the gliadin lowing: sCa: 8.9 (normal: 8.6-10.2), nor- fraction of gluten. Gliadin combines with Director, Saint Barnabas Osteoporosis and results are listed in the table below.
DISCUSSION
sorption. Thus, Mary R.’s celiac disease must would be expected for her age, which sug- PATIENT PROFILE
treated effectively. This case underscores the gests a secondary cause for her bone loss.
Mary R. is a 65-year-old healthy Caucasian importance of a laboratory work-up to rule woman (height 5’ 2”, weight 125 lbs), who out secondary causes of osteoporosis.
recently retired as a secretary. She has had six pregnancies with normal outcomes.
in all ethnic groups. All women should be CASE STUDY 2
taken estrogen. Her history includes long- screened by age 65, while those with risk factors, such as exposure to drugs that may cause bone loss, should be screened earlier.
alcohol intake is minimal. She takes a multi- African American women, Susan’s T-score suggests that she is at significant risk for one glass of milk and one glass of calcium- fractures, while her Z-score suggests a sec- fortified orange juice daily. Her bone min- PATIENT PROFILE
ondary cause of bone loss. In fact, she has eral density (BMD) results are listed in the Susan T. is a 45-year-old African American several risk factors for secondary osteo- high school teacher. Her history includes porosis, including early surgical menopause surgical menopause five years previously.
and chronic exposure to anticonvulsants and She never took estrogen and currently has corticosteroids. In this case, the primary Table 1. BMD Results
culprit was a vitamin D deficiency: vitamin D is critical for calcium absorption. In addition T-scores Z-scores
to reducing calcium absorption, vitamin D phenytoin 300 mg daily. She has had asthma deficiency has adverse neuromuscular effects that significantly increase the risk of falls include a b.i.d. steroid inhaler and oral glucocorticoids 5-6 times per year for 2-6 weeks for exacerbations. She takes a multi- of vitamin D deficiency is anticonvulsant Lab results were normal for serum calcium,phosphorus, alkaline phosphatase, CBC,and differential. Her 25 OH vitamin D was28 ng/mL and 24-hour urine calcium was Table 2. BMD Results
30 mg/24 hr. Tests for antigliadin antibodiesand transglutaminase antibody were strongly T-scores
T-scores
Z-scores
DISCUSSION
This patient’s low Z-score suggests thatsomething other than (or in addition to) postmenopausal bone loss is occurring.
EFFECT results continued
Case Study 2 continued
FORE-Foundation for Osteoporosis Research, noted that there were no clinically apparent of vitamin D. In general, people under age vertebral or hip fractures in either arm, but there were a variety of fractures of the wrist, D daily; for those 70 and older, the recom- shoulder, or toes; these data will be presented at a later date. The discontinuation rate was daily vitamin D intake of 800-1000 units.
In summary, this case is a timely reminderthat not all low bone density is simple osteoporosis. Several potential causes of 1. Kagan R, Greenspan SL, Sackarowitz J, et al. Efficacy of Fosamax vs. Evista Comparison Trial(EFFECT): Results of a randomized, multicenter study. Obstet Gynecol. 2003;101(4 Suppl).
1. Successful osteoporosis therapy can be 5. In the EFFECT trial, alendronate was more 8. The NORA study showed that patients with entirely accounted for by increases in bone T-scores of -1 to -2.49 had a fracture risk almost increasing lumbar spine BMD at 12 months.
double that of patients with normal BMDs.
2. Which of the following is (are) consequences 6. In the retrospective cohort study by Neuner 9. Which of the following is a potential secondary et al, what percentage of women with radio- graphic evidence of vertebral compression D. Disconnection of the trabecular network 7. What is (are) the current recommendations of the National Osteoporosis Foundation for 3. Long-term use of PTH may have undesirable initiating osteoporosis therapy in postmeno- 10. Structured counseling DXA by a specially trained nurse has not been shown to improveoutcomes after DXA.
4. One of the drawbacks of current approaches for assessing bone quality is the absence of Seven correct answers are required for credit
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