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 ofOsteoporosis. 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 AnnualClinical 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)
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-
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-
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
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 Activity Evaluation
1. As a result of the information contained in this activity, will you make any
2. In your opinion, how could this activity be improved? (e.g., change format,
more details, fewer details, discuss other topics, change length)
3. Please rate the educational value/clinical relevance of this activity.
Excellent/outstanding Very good Good/above average
4. Please rate the extent to which the learning objectives were met.
Excellent/outstanding Very good Good/above average
5. Was the material presented objectively and did it avoid commercial bias?
Please submit this form, along with your check for $15.00 payable to OCME and mail in the enclosed envelope to:
OCME RegistrarP. O. Box 980048Richmond, VA 23298-0048
Or you may pay by credit card and fax your form to us at 804-828-7438
Time actually spent on this activity minutes
I have read the newsletter and completed the post-test and activity evaluation.
To earn one (1) hour of category 1 CME credit after readingthis newsletter, please mail the completed post-test answers,activity evaluation, and personal information questionnairein the enclosed envelope. Post-Test Answers
(Circle the appropriate letter for each question.)
Signora Biblioteca Come i lettori avranno visto, la Fondazione Micheletti è nata col fine di salvare dalla dispersione documenti e archivi, del periodo della guerra e delle Lotte di Liberazione, poi dei movimenti popolari, operai e ambientalisti. Di tale politica si fa interprete questa rivista telematica. Quanto siano grandi i pericoli di dispersione di carte, libri, documenti, è testim