CONTENTS

Part 1. Peptic Ulcer Disease. .............................. .I
Introduction  ............................................
Impact of Smoking and Smoking Cessation on Ulcer Occurrence . .
  Smoking and Gastrointestinal Physiology ...................
  Trends in Peptic Ulcer Disease  ...........................
  Morbidity From Peptic Ulcers  ...........................
  Mortality From Peptic Ulcers  ............................
Effects of Smoking on Ulcer Healing and Recurrence  ...........
  Healing of Duodenal Ulcers  .............................
  RecurrenceofDuodenalUlcers ...........................
  Healing of Gastric Ulcers  ...............................
  Recurrence of Gastric Ulcers .............................
Summary ...............................................
Part II. Osteoporosis and Skin Wrinkling .................... .~I.
Osteoporosis.. ..........................................
  Introduction  ..........................................
  Pathophysiologic Framework  ............................
  Bone Mineral Content in Smokers Compared With Nonsmokers
  Smoking as a Risk Factor for Osteoporotic Fractures ..........
  Smoking Cessation and Osteoporosis and Fracture  ...........
  Summary  ............................................
SkinWrinkling.. ........................................
  Introduction  ..........................................
  Pathophysiologic Framework  ............................
  Smoking and Skin Wrinkling  ............................
  Smoking Cessation and Skin Wrinkling  ....................
  Summary  ............................................

Conclusions  ..............................................

References  ...............................................

........ 429

........ 429

........ 319

........ 429

........ 430

........ 431

........ 432

........ 331

........ 331

........ 433

........ 440

........ 440

........ 441


........ 433

........ 443

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........ 453

........ 453

........ 453

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........ 455

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. . . . . 459

327


PART I. PEPTIC ULCER DISEASE

Introduction

Numerous studies have demonstrated the association between smoking and the
occurrence of peptic ulcer disease. This association was noted in the 1964. 197 I. and
1972 Surgeon General's Reports (US PHS 1964: US DHEW I97 I. 1972). The 1979
Report stated that the evidence of an association between cigarette smoking and peptic
ulcer was strong enough to suggest a causal relationship (US DHEW 1979). That
Report concluded that cigarette smoking was associated with the incidence of peptic
ulcer disease and with increased risk of dying from peptic ulcer disease: the evidence
that smoking retards healing of peptic ulcers was regarded as highly suggestive. The
1989 Report (US DHHS 1989) stated that smoking cessation may reduce peptic ulcer
incidence and is an important component of peptic ulcer treatment. even with the
effective drug therapy presently available. This Section focuses on smoking cessation
and the occurrence and course of peptic ulcer disease.

Impact of Smoking and Smoking Cessation on Ulcer Occurrence

Smoking and Gastrointestinal Physiology

Kikendall. Evaul, and Johnson (1984) reviewed the effect of cigarette smoking on
aspects of gastrointestinal physiology relevant to peptic ulcer disease. The literature
available at the time of their review supported the following concepts. Chronic cigarette
smokers have higher maximal acid output than nonsmokers. Smoking I cigarette or
more has no consistent immediate effect on acid secretion.  Smoking 1 cigarette
immediately decreases alkaline pancreatic secretion and immediately results in a
pronounced fall in duodenal bulb pH, especially in subjects with gastric acid hyper-
secretion. Smoking has a variable effect on gastric emptying, depending on experimen-
tal design. Smoking increases duodenogastric reflux.  Smoking decreases gastric
mucosal blood flow. Smoking during waking hours inhibits the antisecretory effects
of a nocturnal dose of cimetidine, ranitidine. or poldine.

Subsequent to this review, the two latter concepts have been seriously challenged.
Robert, Leung. and Guth ( 1986) found that neither nicotine nor smoking inhibited basal
gastric mucosal blood flow in rats.  Several investigators could not confirm that
smoking antagonized the antisecretory effect of cimetidine or ranitidine (Deakin.
Ramage, Williams 1988: Bianchi Porro et al. 1983: Bauerfeind et al. 1987).

However, several of the findings from this earlier review (Kikendall, Evaul, Johnson
1984) have been confirmed by more recent reports.  Parente and associates (1985)
confirmed higher pentagastrin-stimulated acid secretion among chronic heavy smokers
than among nonsmokers. Smokers also had higher basal serum pepsinogen-I levels.
These differences were statistically significant and large enough to be of clinical
importance. Higher maximal gastric acid secretory rates among smokers compared


v. ith non\mohers were al\o demonstrated by Whitfield and Hobsley ( 19X5) in a study
of 201 patient\ M ith duodenal ulcer.

Additionall). Mueller-Lissner ( 1986) noted that chronic smokers M.ho abstained from
smohing for I2 hours had more duodenopastric bile retlux than nonsmoher\ and
confirmed that smoking cigarettes acutely augments the already elevated rate of bile
reflux. Quimby and coworkers (1986) reported that active smoking transiently
decreased gastric mucosal prostaglandin synthesis.

In summary. the known effects of smoking on gastroduodenal physiology provide
multiple potential mechanisms for enhancement of an ulcerdiathesis by active smoking.
Several of the effects of smoking, most notably the inhibition of alkaline pancreatic
secretion. the reduction of duodenal bulb pH, and the reduction of prostaglandin
synthesis. are transient effects that could be reversed quickly by abstinence from
smoking.

Trends in Peptic Ulcer Disease

During the past several decades. the rates of hospitalization for and mortality from
peptic ulcer disease in the United States have declined dramatically (Kurataet al. 19X3).
Although changes in coding practices and/ordiagnostic procedures could explain some
of the decline, the trends in mortality from peptic ulcer have paralleled the decreasing
prevalence of smoking. Kurata and coworkers (1986) studied trends in ulcer mortality
and smoking in the United States between 1920 and 1980 and estimated that the portion
of duodenal-ulcer-related mortality attributable to smoking was between 33 and 63
percent for men and 25 and 50 percent for women. In contrast, Sonnenberg ( 1986)
concluded that smoking was not the main determinant of the birth cohort phenomenon
of declining peptic ulcer mortality in the United Kingdom. This study descriptively
compared the death rates for duodenal and gastric ulcer with the annual cigarette
consumption in the United Kingdom according to birth cohorts and found a lack of
correlation between ulcer mortality and cigarette consumption (Sonnenberg 1986).
Thu\, factors in addition to cigarette smoking may also underlie the recent trends in
these indicators of peptic ulcer disease.

Two factors that have receivedconsiderable attention in recent years are Hc~lic~ohtrc~tcr~
py/orV gastritis (Graham 1989) and the use of nonsteroidal anti-inflammatory drugs
(Griffin. Ray. Schaffner 1988). Martin and associates ( 1989). in an endoscopic stud).
found that smoking was a risk factor for peptic ulcer disease among patient\ who had
Hc~lic~ohut~er plori gastritis. Willoughby and colleagues ( 1986) found that smoking
Was associated wnith peptic ulcer disease among subjects with rheumatoid arthritis. most
of whom were taking nonsteroidal anti-inflammatory drugs. Ehsanullah and colleagues
( 1988) and Yeomans and associates ( 1988) also showed an association of smoking with
the acute gastric erosions and submucosal hemorrhages induced by these drugs. The\e
studies demonstrated that smoking is associated with ulcer disease related to both
Helic~ohut~fer./~~/or.i and nonsteroidal anti-inflammatory drugs.

430


Morbidity From Peptic Ulcers

In an analysis of prospective cohort data on ulcer incidence in women from the
National Health and Nutrition Examination Survey 1 Epidemiologic Follouup Study.
the relative risk for developing peptic ulcer was I.3 amon? former smoherc (Y5-percent
confidence interval (Cl). 0.7-3.`)) and I.9 among current smoher\ (c)5-percent Cl.
1.2-2.6) compared with lifetime nonsmokers (Anda et al. 1990). In this study. former
smokers were defined as persons who had smoked at least IO0 cigarettes in their lifetime
but who were not smohing at the time of the baseline interview. The mean length of
followup in this cohort was Y years. This analysis used the Cox proportional haLards
model to adjust for the potential confoundin effects of age. sex. socioeconomic status.
regular aspirin use. alcohol intake. and coffee consumption.

Ainley and associates (19X6) surveyed the smoking behavior of I.217 patients
undergoing endoscopy. This study did not include "normal" or community controls as
all patients had indications for endoscopy. Of the smokers. I I.Y percent had gastric
ulcers. a diagnosis shared by 7.7 percent of ex-smohers (p<O.O25) and 4.6 percent of
never smokers (p<O.(X) I ). Of the smokers. 12.X percent had duodenal ulcer compared
with 6.X percent of ex-smoker\ (p<O.Ol ) and 6. I percent of never smohers (p<O.OOI ).

In a study of nearly 6.000 Japanese men living in Hawaii (Stemmermann et al. IYXY).
243 developed gastric ulcers and 99 developed duodenal ulcers in 20 years of followup.
Gastric ulcer developed amon g 6.7 percent of current smoker\ compared with 3.X
percent of former smokers and 3.2 percent of lifetime nonsmokers (p<O.OOOl).
Duodenal ulcer developed more often (p<O.OOOl ) among current smokers than among
former smokers or never smokers (2.7 vs. 1.4 vs. 0.9 percent. respectively).

These three studies show that smokers are more likely than never smokers and former
smokers to develop peptic ulcer disease. Two of the studies show higher frequencies
among smokers for both duodenal and gastric ulcer. All three studies demonstrate that
the risk of peptic ulcer for former smokers is between that for current smokers and for
never smokers. The tendency of symptomatic smokers to stop smoking would bias the
results of such studies toward reducing the apparent benefit of cessation (Chapter 2).
These studies strongly suggest that the smoker's risk of developing either gastric or
duodenal ulcer is diminished after smoking cessation.

In an early analysis of cross-sectional survey data among men aged 20 to 79 in
Tecumseh. MI (Higgins and Kjelsberg 1967). the age-adjusted prevalences of self-
reported peptic ulcer among nonsmokers (presumably never smokers), ex-smokers. and
current smokers were 5.2, X.0, and 7. I percent. respectively. The definitions of smoking
status were not presented, and the differences were not statistically significant. In this
study. the prevalences of peptic ulcer among women who were nonsmokers. ex-
smokers. or current smokers were I .4. I .5. and 2.X percent. respectively: these differen-
ces were reported as statistically significant between smokers and nonsmokers (Higgins
and Kjelsberg 1967). Earlier studies such as this. which were conducted before the
advent of endoscopy. had relatively poor diagnostic accuracy and may consequently
have been biased toward underestimating the effects of smoking.

Additional reports linked smoking to some of the complications of peptic ulcer
disease. For example. X6 percent of 12X patients pre\enting with perforated duodenal


ulcer were cigarette smokers compared with 5 I percent (p<O.Ol ) of retrospectively
matched controls (Smedley et al. 1988). Other reports noted that smokers comprised
87 percent (Heuman. Larsson, Norrby 1983) and 86 percent (Hodnett et al. 1989) of
patients with perforated duodenal ulcers and X3 percent of males undergoing surgery
for peptic ulcer (Ross et al. 1982). These latter studies were uncontrolled, and the high
percentages of smokers have not been confirmed in some other surgical series. Never-
theless, these latter studies support the findings of Smedley and associates (1988) and
suggest that smokers with peptic ulcer who continue to smoke may be at greater risk
for ulcer complications than nonsmokers.

Mortality From Peptic Ulcers

The American Cancer Society Cancer Prevention Study I (ACS CPS-I) found that
the relative risk of mortality for peptic ulcer among men was 3. I for current smokers
(95-percent Cl. 2.2-4.2) and 1.5 for former smokers (95-percent CI, I .O-2.3)compared
with lifetime nonsmokers (US DHHS 1989).

In the U.S. Veterans Study, the duodenal ulcer morfality ratios for current and
ex-smokers compared with never smokers were 3.2 and 1.8, respectively (Kahn 1966).
Ex-smokers in this report were persons who stopped smoking for reasons other than
physician's orders but were otherwise not clearly defined. The mortality ratios for
gastric ulcer among current and ex-smokers were 4. I and 3.4. respectively. Although
these differences in mortality were not statistically significant. the trends were similar
to those in ACS CPS-I and supported the results of that study.

Effects of Smoking on Ulcer Healing and Recurrence

Healing of Duodenal Ulcers

Numerous trials evaluating ulcer therapy have suggested that smoking adversely
affects ulcer healing. Kikendall, Evaul, and Johnson ( 1984) reviewed the results of IX
studies that assessed the impact of smoking on healing of duodenal ulcers. In most of
these studies. the percentage of healed ulcers was lower among current smokers than
among nonsmokers (Table I ). These studies were not explicitly designed to study
smoking. and the nonsmoking category presumably included never as well as former
smokers. When the data from these studies were subjected to meta-analysis, the
percentage of healed ulcers was lower among smokers than among nonsmokers in
patients treated with Hz-blockers (p<O.OOOl) and in patients given placebo (p<O.OOOl)
(Table 2). The median difference in percentage of subjects completely healed was 22
percentage points in favor of nonsmokers in groups treated with Hz-blockers, 21.5
percentage points in groups receiving other active therapy, and 22 percentage points in
groups receiving placebo. The data for groups receiving active therapy other than
Hz-blockers were not subjected to statistical analysis because the data were not
homogeneous, but the data in Table I show that nonsmokers in most of these other
treatment groups fared better than their smoking peers. Most trials published since this

432


1984 review show similar trends toward greater likelihood of healing of duodenal ulcers
in nonsmokers.

Recently, several reports have suggested that sucralfate (Lam et al. 1987) and
misoprostol (Lam et al. 1986) may have particular value in treating duodenal ulcers
among patients who smoke. Lam (1989) has compiled a list of six studies showing
comparable duodenal ulcer healing rates for smokers and nonsmokers treated with
sucralfate. Although a few studies offer contrary data (Van Deventer. Schneidman,
Walsh 1985; Martin 1989). much of the evidence suggests that sucralfate heals
duodenal ulcers in smokers and nonsmokers at comparable rates.

The claim that the efficacy of prostaglandins for duodenal ulcer healing is unaffected
by smoking is based on the results of a single study (Lam et al. 1986). The design of
this study is unusual because patients who smoked were encouraged to abstain from
smoking during the study; therefore. healing efficacy in smokers may have been due to
the combined effects of misoprostol and smoking cessation. Other duodenal ulcer
treatment trials (Bianchi Porro and Parente 1988: Brand et al. 1985; Nicholson 1985)
showed improved healing among nonsmokers. Nicholson ( 1985) treated duodenal
ulcer patients with 200 1-18 misoprostol4 times daily and documented healing in 73 of
138 smokers (53 percent) and 66 of 93 nonsmokers (71 percent, p<O.Ol). Thus, the
evidence is tenuous at best that oral prostaglandins can overcome the adverse effects
of smoking on the healing of duodenal ulcers.

Other recently reported clinical trials are not systematically reviewed in this Chapter.
Most of the recent trials that have analyzed the effects of smoking on duodenal ulcer
healing show lower healing rates among smokers than among nonsmokers.

In contrast to the numerous comparisons of duodenal ulcer healing rates among
smokers and nonsmokers, only one study has examined specifically the effect of
smoking cessation on duodenal ulcer healing (Hull and Beale 1985). In this study, 70
male smokers with duodenal ulcers were advised to stop smoking and were treated with
cimetidine for 3 months. Those who stopped were no more likely than those who
continued smoking to have healed their ulcers on endoscopic exam at 3 months (75 vs.
8 I percent, respectively, not significant).  Cimetidine treatment was then stopped.
Three months later. 72 percent of those who quit smoking and 39 percent of smokers
were ulcer-free at repeat endoscopy (p<O.OS) (Hull and Beale 1985). Although these
results require confirmation, the findings suggest either that some of the adverse effects
of smoking on duodenal ulcer disease may persist for a few weeks after cessation of
smoking or that cimetidine therapy may mitigate these effects.

Recurrence of Duodenal Ulcers

A number of prospective clinical trials of maintenance therapy for duodenal ulcer
have assessed the impact of smoking on ulcer recurrence. In one of the larger trials
(Sontag et al. 1984). 370 subjects with previously documented duodenal ulcer. who had
no active ulcer at enrollment endoscopy. were randomized to placebo or cimetidine.
Endoscopy was repeated at 6 and I2 months or whenever dyspepsia occurred during
the I2 months of follow up. In the placebo group. smokers were more likely than
nonsmokers to experience recurrence (72 vs. 21 percent. p<O.OOI ). In addition.


TABLE l.-Percentage of healed duodenal ulcers among smoking and nonsmoking patients

Patient5 with henled ulcers

Reference               Drug

Duration of Rx
  (Wh)

Exclu\ivrly Hdkcker therapy

Bianchi Porro et al. ( IYX I )
Korman et al. ( IYX3)
Korman. Hanky et al. ( 19X'-)
Hrtxl et id. ( lY7X)
Korman et al. ( 19X I )
Marks et al. ( IYXO)
Bardhan ct al. ( 1Y7Y)
Guglcret A. (19X2)
Gugler et al. ( IYX?)
Korman, Hetlel et aI. (IYX2)
Korman, llrt/el ct al. ( IYXZ)

H:-hIocher\
H:-hlochcr\
R:untdmt2

CmvAline

Cimetdine

Cimetdine
Cimetidine

Cimetidine

Oxmctidine

Oxmettdine

Ctmrtidme

4

4-b

4

h

h

6

4

X

X

4

4

76      66

71      62

13     h3,

43      Xh

IO      50

I Y      7x

94      h.5

33      b4

35      71

27      70

2x      6X

3h      X6

h4      YS

12     IO0

43      x0

I.5     loo

IO      ho

30      hS

lb      94

14      Y3

IS      x7

I3      Y2

40.5

4.0 I

4.05

NS

<o.os

NS

NS

<o.os

NS

NS

<o.os


TABLE I.-Continued

Patients with healed ulcers

Reference               Drug

Duration of Rx
  (W

  Smokers         Nonsmokers                Difference in
N"    sh       N"    P/rh      p-value     % healed

Active therapy other than Hz-blockers

Bianchi Porro et al. (19X0)
Sonnenherg et al. ( IYX I)


Barbara et al. ( lY79)
Vantrappen et al. (lYX2)
Peterwn et ill. (1977)
Korman et al. ( I YX I )
Marks et al. (1980)
Nagy (lY7X)
Young and St. John (IYXZ)
Lametal.(lY70)
Lam et al. (lY7Y)

Mu\wrrut and Eisrnmann

(IYUI)

Cimetidine or pirenzepine
Cimetidine, pirenzepine. ot
placebo
Pirenzepine
Arbaprostil
Antacid

Antacid

Sucralfate

Carbenoxolone

Carbenoxolone
Antacid + sulpiride
Placebo or sulpiride
Antacid

4

4

63      71         27      XI

66      54        68      73

I6      69        28     43

68     65         I4      79

28      7s         x      xx

I3      39        I2      67

20      90         Y      67

II      55         10      x0

I4      so         6      x3

I7      59        s4      YI

I5      27        3s      51

56      4x        24      7.5

NS         IO

<o.os         I9

NS        -26

NS        I4

NS        I3

<o.os        2x

NS        -23

NS        25

NS        33

`co.05        32

NS        24

<o.os        27


TABLE L-Continued

Krference


Placebo therapy

Drug

Duration of Rx
  (wk)

     Patients with healed ulcer\

  Smokers          Nonsmoker5                Diftct-encc in
N"    c/rh       N"    Qh      p-value      % healed

Bianchi Porro ct al. (10X0)
Nqy (lY7X)
Young and St. John t 19x7)
Ha/cl et al. (11)7X)
Peterson et al. (1977)
Vantrapprn et al. (IYX2)
Barham et al. ( lY7Y)
Korman. Han&y c't nl. ( IYX2)
Bianchi Porro et al. ( IYX I)
Bardhan ct al. ( IY7Y)

Plawbo

Placrho

Pl;&w

Pl;UTbo

PIXLAX~

Placeho

Placebo

Placebo

Placebo

PlLIcebo

5s      31

II      2.7

IS      20

42      37

2s      32

6S      2x

2.5      2x

I4       0

62      24

33      24

IS      53

I I      30

5      40

42      42

I3      6Y

26      65

I 0      so

II      36

20      so

I3      3x

NS

NS

NS

NS

<o.os

<o.os

NS

4.05

4.0 I

NS

27

5

`0

5

37

37

22

Xl

76

II


TABLE 2.-Results of statistical analysis of pooled data from Table 1

Percentage healed

Smokers          Nonsmoker\

N"    Qb       N"    ?ch

Test
\tatlitic
Z    p-value

All patient groups
Hz-blockers
Placebo

Subset of large patient groups
H?-blockers
Placebo

449      70        27x      90     7. I     <o.oao I
341      2x         I66      JY     4.6     <o.ooo I



284      70        IX3      XY     5,s     <O.orwl
I49      29         8X      51      3.4     <o.oo I 2

"N=tml followed m \mokmg categor)
h%=percenrage of total who experienced healed ulcer\ -1thm qeclfwd t!mr
SOLRCE:  Kikendall. Evaul. Johnwn llYX11

smokers receiving cimetidine were as likely to experience recurrence as nonsmokers
receiving placebo, leading the authors to conclude that for smokers, quitting smoking
may be more important in the prevention of ulcer recurrence than receiving cimetidine
treatment (Sontag et al. 1984). Table 3 displays the results of similar prospective,
controlled trials of the recurrence of duodenal ulcer identified in a literature search
performed in March 1990. Trials or treatment groups with fewer than 12 smokers or
I2 nonsmokers and reports that did not provide the raw data relative to smoking were
omitted. Smokers had more recurrences than nonsmokers in every trial or every
treatment group, regardless of the treatment (even surgery) and prophylactic therapy
used to achieve healing. The difference was statistically significant in about half of the
studies.

The only study of larger size that failed to show even a nonsignificant advantage for
nonsmokers was an Australian community-based study, not included in Table 3 because
the requisite raw data were not published (Nasiry et al. 1987). This study differed from
most of those listed in Table 3 in several ways, including larger numbers of exclusions.
4l-percent withdrawals, primary reliance on symptoms rather than endoscopy to
document recurrences, and lack of systematic effort to control the use of medications
that may affect ulcer recurrence. Factors such as these may explain the disparate results.

One trial listed in Table 3 found that incremental increases of cigarette consumption
were significantly associated with greater risk of duodenal ulcer recurrence (Korman
et al. 1983). Massarrat. Mtiller, and Schmitz-Moormann (1988) and Piper, McIntosh
and Hudson (1985) also found that the number of cigarettes smoked per day was a
significant predictor for ulcer recurrence. Although these studies were designed to
assess risk factors for recurrence of duodenal ulcer. the latter two studies are not listed
in Table 3 because one did not present the necessary raw data (Massarrat. Miiller.
Schmitz-Moormann 1988) and the other (Piper. McIntosh. Hudson 1985) had a study,
design that differed from that of the studies listed in Table 3.


TABLE 3.-Recurrences of duodenal ulcer in smokers and nonsmokers in clinical trials

Reference                Prophylaxlh

Followup
(ml

Smokers               Nonsmoker\

N'     sh         N"     Qh        p-~"IUC

Sontag et al. ( 19X4)
Bianchi Porro et al. (19X2)
Lauritsen et al. (10x7)
Gihinski et al. (19X4)
Cerulli et al. (IYX7)
Brunner ( I YXX)
Lauritsrn et al. (19x7)
Sonnenherg et al. ( 19X I )
Battaglia et al. (19X4)
Paakkonen et al. (IYXY)
Bynum and Koch (19x9)
Cla\\en et al. ( I YX3)
Graffner and Lindell ( IYXX)
Rydninp et al. ( IYXZ)
Sontng et al. (19x4)
Balm et al. (lYX7)
Marks et al. ( I YX9)
Paahkonrn el al. (IYXY)
Bynum and Koch (IYXY)
Classen et al. (IYX3)
Cerulli et al. (IYX7)

Cimetidine

Cimetidine

Ranitidine

Ranitidine

Nwatidine

Roxatidine acetate
Enprostil
Various

Various

Sucralfate

Sucralfate

Sucralfate
Parietal cell vagotomy
Diet

Placeho

Placebo

Placebo

Placebo

Placebo

Placebo

Plncebo

I2

I2

I2

I2

6

I2

12

I2

I2

4

6

60-16X

6

I2

I2

I2

I2

6

IX6

6h

4x

62

I.39

4x

.s2

33

46

I3

5X

27

I YO

5s

3Y

13

21

I6

so

30

I46

34

s9

33

4.5

I7

4x

6.5

52

30

69

45

2s

24

69

72

X.5

95

XX

XI

62

37

I I4      IX           <o.o I

40      42           NS'

21      19            NS

I23      II          <o.oos

11x      4           0.00 I

41      20           <o.o I

I4      so            NS

33      33            NS

24      ?I             NS

IO      47            NS

64      3Y             NS

51      IX             NS

I I6       7           <o.o I

IX      39           40s

31      21           4l.00 I

I3      77            NS

I2      67           <o.os

24      67            NS

67      so           40 I

4.5      41             NS

I IO      2s            0.05


TABLE 3.--Continued

Recurrences

Reference               Prophylaxi\

tl;dlcrhoch et al. (IYX7t"           None
Kornlan et al. ( I OX.?)             None
I~alll Cl al. ( 10x7 I               None
I.cc. Samloll. Hardman ( IYXS)        None

KocI/ and Hallct ( IYXY)           None

Followup
(mu)


  I2

  I1

  24

  4

  I2

Smohcr5              Nonsmoker\

N'l     `/h         N"     vh       p-value


III       x0          I47      5x          4.00I

4s       X-l           60      53           <o.o I

h(l      IW          17x     14'          <o.os

5x      hY           4Y      4s           <o.os

25       64          2X      so            NS


Healing of Gastric Ulcers

Doll, Jones. and Pygott ( 1958) studied 80 smokers hospitalized with gastric ulcer.
Of these, 40 randomly chosen patients were advised to stop smoking; the remaining 40
did not receive advice regarding smoking. As assessed by barium examination, the
average reduction in ulcer crater size at 28 days was 78.1 percent among those advised
to stop smoking and 56.6 percent among those not advised to stop (~~0.05). The
reduction in crater size was 83.2 percent among smokers who stopped smoking
completely versus 71.8 percent among those advised to stop but who did not do so.
Most of the latter group substantially reduced their tobacco consumption during the
trial. This study indicates that gastric ulcer patients who stopped or reduced smoking
after receiving medical advice responded much better to treatment than smokers who
were not advised to stop (Doll, Jones, Pygott 1958). This study, performed in the era
before the availability of potent antisecretory agents, suggests that smoking cessation
alters the natural history of gastric ulcer among smokers.

These findings have been confirmed by Tatsuta, Iishi, and Okuda (1987). Sixty-four
Japanese outpatients with endoscopically proven gastric ulcer were treated with ant-
acids and dicyclomine hydrochloric acid. Additionally, half of the 40 smokers were
advised to stop smoking or to reduce smoking by at least one-half. Advice regarding
smoking was not given to the remaining smokers. Endoscopy was repeated in I2 weeks
by an endoscopist who was unaware of the patients' symptoms or smoking status.
Ulcers had healed in I I of I? smokers (92 percent) who stopped or reduced smoking
and in 7 of 28 smokers (25 percent) who continued to smoke at their pretreatment level
(p<O.OOl). Ulcers also healed in 60 percent of nonsmokers (Tatsuta, Iishi, Okuda
1987).

A retrospective study (Herrmann and Piper 1973) that employed air contrast radiog-
raphy to assess ulcer presence and size in 101 gastric ulcer patients found mean
decreases in ulcer size at 3 weeks of 69,73, and 84 percent, for smokers who continued
to smoke. smokers who stopped smoking, and nonsmokers, respectively. Although
seeming to support the findings of Doll, Jones, and Pygott (1958) and Tatsuta. Iishi.
and Okuda (1987). these differences were not statistically significant (Hermann and
Piper 1973). The ulcer size at entry into this study was three times as great among
smokers as among nonsmokers, rendering inappropriate a comparison of the time
required for complete healing among groups.

Only these three clinical studies have assessed the benefits of smoking cessation on
the healing of gastric ulcer: all three demonstrate or suggest a benefit. In contrast, recent
randomized therapeutic clinical trials have generally shown no advantage in gastric
ulcer healing for nonsmokers compared with smokers (Wright et al. 1982; Kellow et
al. 1983: Farley et al. 1985: Euler et al. 1989; McCullough et al. 1989).

Recurrence of Gastric Ulcers

Tatsuta, Iishi, and Okuda (1987) evaluated the effect of smoking cessation on the
recurrence of gastric ulcers for 47 participants who had an endoscopically proven
gastric ulcer within the previous 6 months but who were ulcer-free at entry into the trial.

440


All were treated as outpatients with antacids and dicyclomine hydrochloric acid. Half
of the smokers were advised to stop smoking or to reduce cigarette consumption by at
least one-half. The remainder were not given this advice. Endoscopy was repeated at
3 and 6 months or whenever symptoms recurred. Data for seven patients who failed to
complete the trial were not presented or analyzed. Ulcers recurred among 9 of 12
patients who continued to smoke at their previous level and in 3 of 13 patients who quit
or substantially reduced their smoking (75 vs. 23 percent, ~~0.05). An ulcer recurred
in I of 15 (7 percent) nonsmokers (Tatsuta. Iishi. Okuda 1987).

This is the only prospective, controlled study that has evaluated the effect of smoking
cessation on gastric ulcer recurrence. However, the reports of several clinical trials of
maintenance therapy for gastric ulcer have provided data on the impact of smoking on
the trial results. All such prospective, controlled clinical trials are displayed in Table
4. Although several of these trials or treatment groups are small, every treatment group
shows an advantage for nonsmokers. In two trials, the difference was statistically
significant. The median percentage difference in recurrences for smokers compared
with nonsmokers is 20 percentage points.

Summary

The known effects of smoking on gastroduodenal physiology include several
mechanisms that might enhance an ulcer diathesis. Most of these mechanisms are
rapidly reversible upon cessation of smoking. The association of smoking with in-
creased maxima1 gastric acid secretory capacity has not been assessed for reversibility.

Epidemiologic studies consistently demonstrate that current smokers compared with
nonsmokers are at increased risk for occurrence of and death from duodenal and gastric
ulcer. The risks for former smokers are generally found to be between those of current
smokers and nonsmokers.

Duodenal ulcers are less likely to heal within specific time intervals among smokers
than among nonsmokers, regardless of whether patients are treated with placebo or most
active therapies. Both gastric and duodenal ulcers are more likely to recur within
specified periods of observation among smokers compared with nonsmokers.

A limited number of clinical trials have been performed to assess the effect of
smoking cessation on the course of peptic ulcer disease. These show that smoking
cessation, or in some trials, substantial reduction of daily cigarette consumption. is
associated with fewer duodenal ulcers at 6 months but not at 3 months, with improved
short-term healing of gastric ulcers. and with reduced recurrence of gastric ulcers.


TABLE A.-Recurrences of gastric ulcer in smokers and nonsmokers in clinical trials


PART II. OSTEOPOROSIS AND SKIN WRINKLING

Osteoporosis

Introduction

Osteoporosis is a condition of reduced bone mass that increases the risk of fractures.
especially of the hip, distal forearm, and vertebrae, after minimal trauma (Consensus
Conference 1984). The most devastating outcome of osteoporosis is hip fracture,
occurring in over 200.000 persons each year in the United States (Haupt and Graves
1982: Lewinnek et al. 1980). Mortality in the first years after hip fracture is increased
IS to 20 percent (Cummings and Black 1986: Gallagher et al. 1980; Jensen and
Tsndevold 1979: Lewinnek et al. 1980: Miller 1978). Results from three studies
indicate that approximately IS to 25 percent of previously functionally independent
persons who sustained a hip fracture remained in a long-term facility after I year, and
25 to 35 percent of those who returned home after a hip fracture required help in
performing daily activities (Campbell 1976; Jensen and Bagger 1982: Thomas and
Stevens 1974).

Osteoporotic forearm and vertebral fractures also have been found common among
the elderly. Most cases do not require hospitalization or result in long-term disability
(Ga  cay et al. 1979: Owen et al. 1982): however. the cost of caring for these fractures
has been estimated to be $ I40 million per year (Melton and Riggs 19X3).

Established risk factors for osteoporotic fractures include advanced age. white race.
female sex, number of years since natural or surgical menopause. slender body build.
prolonged immobilization, alcohol use. and use of certain medications (Cummings et
al. 198.5). Postmenopausal estrogen replacement therapy decreases the risk of os-
teoporotic fractures: this risk reduction is greater with longer duration of treatment
(Weiss et al. 1980).

Pathophysiologic Framework

Smoking may alter risk of osteoporosis and fracture through several mechanisms.
First. bone loss accelerates at menopause (Lindquist and Bengtsson 1979: Lindquist et
al. I98 1: Paganini-Hill et al. 198 I; Richelson et al. 1984: Mazess 1982). and smokers
undergo menopause I to 2 years earlier than never smokers (Chapter 8). Second. a thin
body build increases risk of osteoporotic fracture (Daniel] 1976: Hutchinson, Polansky.
Feinstein 1979; Kiel et al. 1987; Paganini-Hill et al. I98 I : Williams et al. 1982; Wyshak
l981), and smokers generally weigh less than nonsmokers (Chapter IO). Third,
smoking has been reported to reduce the endogenous production of estrogen (Mac-
Mahon et al. 1982) and increase its metabolism (Jensen. Christiansen. Rodbro 198.5:
Michnovicz et al. 1986).

Smoking also may decrease the effectiveness of exogenous estrogens (Daniel] 1987).
Endogenous estrogen metabolism is widely believed to affect the risk of osteoporosis
and fracture. and exogenous estrogen use is firmly linked with lower rates of
postmenopausal bone loss and lower risk of hip, forearm. and vertebral fracture among


women (Ettinger, Genant. Cann 1985; Hutchinson, Polansky, Feinstein 1979: Kreiger
et al. 1982; Paganini-Hill et al. I98 I ; Weiss et al. 1980: Riis. Thomsen. Christiansen
1987: Kiel et al. 1987). However, a I - to 2-year shift in age at menopause probably
does not alter the risk of osteoporotic fracture substantially. Not all researchers have
found differences in endogenous estrogen levels between smokers and nonsmokers
(Crawford et al. 1981; Friedman, Ravnikar, Barbieri 1987). Although therapy with
exogenous estrogen reduces the risk of osteoporotic fractures among women (Ettinger.
Genant, Cann 198.5; Hutchinson, Polansky, Feinstein 1979; Kreiger et al. 1982:
Paganini-Hill et al. I98 I; Weiss et al. 1980: Riis, Thomsen, Christiansen 1987; Kiel et
al. 1987), it is not certain whether levels of endogenous estrogen are lower in women
with osteoporosis than in women without osteoporosis (Cauley et al. 1986: Davidson
et al. 1983). The likely effects on osteoporosis and fracture risk of smoking-related
changes in circulating levels of male sex hormones, if such changes occur (Chapter 8.
Part 1). are impossible to predict.

Bone Mineral Content in Smokers Compared With Nonsmokers

Susceptibility to fractures is increased by a reduction in bone mass. Smoking has
been studied extensively in relation to various measurements of bone mass.

Using radiographs of the hand, Daniel] (1976) measured percent cortical area (PCA)
of the second metacarpal midpoint in I03 women aged 40 to 49 years and in 208 women
aged 60 to 69 years.  Smoking was associated with lower PCA among older women,
but there was no difference in PCA between smokers and nonsmokers among younger
women. PCA loss was estimated in 80 of the women aged 60 to 69 by comparison
with averages for the younger women. Smokers had significantly greater PCA loss
per year after menopause compared with nonsmokers (1.02 vs. 0.69 percent/ year.
respectively, p<O.OOl). Nonobese smokers had greater PCA loss per year compared
with nonobese nonsmokers, but obese smokers and obese nonsmokers did not differ
in PCA loss. In both smokers and nonsmokers, nonobese women lost more PCA per
year after menopause than obese women. None of these comparisons controlled for
age or years since menopause.

Since this first report describing "osteoporosis of the slender smokers," at least 21
other studies comparing bone mass in smokers and nonsmokers have been published
(Table 5). Nine of the nineteen studies found lower bone mass in smokers compared
with nonsmokers (Aloia et al. 19X8: Hello, Gergely. Boross 1979: Jensen, Christiansen.
Rodbro 1985: McNair et al. 19X0: Mellstrom et al. 1982; Rundgren and Mellstrom
1984: Sparrow et al. 19X2: Suominen et al. 1984: Slemenda et al. 1989). and the
difference was statistically significant in all but one of these nine studies (Suominen et
al. 1984). The populationba5ed studies by Mellstrom and associates (1982) and
Rundgren and Mellstrom ( 19X-I) are noteworthy because they controlled for potentially
confounding variable\. In both studie\. bone mass was measured by dual photon
densitomrtry of the heel. Mell\triim and colleagues (19X3) reported that bone mass of
the heel was significantly lower in smokers than in nonsmokers. Rundgren and
Mellstrom ( 19X-I) reported IO to 70 percent lower bone mass in male smokers and IS
to 30 percent lower bone ma\s in female smoker\.


TABLE S.--Summary of studies of smoking and bone mass

Reference

Ho116. Ccrfrlj
BorOh\ ( I Y7Y)

McNar et al.
(IYXO)

Population

Bone measurement            Fmding\

l.mtlqui\t et aI.    I.30 women in it
(IYXI)       populatw-had ady in
           SWL?dt?fl

Llndcl-pSrd     I26 healthy voIuntwr\
(IYXI)       uged 20-h')

PCA trom x my of the right 2nd
metacarpal

Women aped 404Y yr: no aeociution
of wwhing 210 ciglday for 25 yr nnd
PCA: women aged 60-6Y yr: vnohers
had lower PCA than nonsmoker\"

BM by DPA at 3rd
lumbar vrrtehrur

BM by SPA of mid\haft
of forearm


TABLE S.--Continued

Referencr

Popul;ttion

Mellstrtim et al.
(IYX?)

Lindquial
(IYXZ)

Sparrow et ill.
(19X?)

Rundgren and
Mellstrixn
(IYX4)

Suominrn et 31.
(IYX4)

Johnell and
Nilaon
(1984)

ZS7 men in a popul:ltion-hahed
study in Sweden

I .JhZ women in a
populnlloll-baaed \lUdY I"
Sweden

33 I men aged 40 x0 ti,llowcd
for 3-S yr

409 men and SSY women horn
m I YO IH)? or I YOh~)7 from 3
populntlon-hnwd study I"
SWdUl

142 me,, aged 3 I -7s

3YS 49.yr-old white women
randomly selected from
participants in a
population-based study in
SWttdNl

Bone meawrement

RM hy DPA a heel

HM hy DPA at 31-d lumbar
vertebrae

PCA x ray ot right ?nd metacarpal
performed at hawline and 3-S yr
later

BM hy DPA at heel

BM hy yray attenuatwn in the
calcaneums

BM hy yabwrptiometry at the
mdiu\ I cm and 6 cm proximal to
the ulnar \tyloid

Findings

BM Iowcr in smokers v\.
non\mokeri'

Stratifying hy age and menopausal
status. no difference in BM between
smoker\ and non~mohen

At baaelme. no dtffrrrnce between
PCA in smokers and nonsmoker\:
wer the 3%S-yr perwd. smokers lost
more PCA than nonsmokers"
(B=-O. 14X. p=O.O3)

BM in wnmen was IS-30% lowrr m
smokers vs. nonsmoker\" and in men
1%Xl'% lower in smokers vs.
nonwlokera": no difference between
ex-cmokerb and smokers

BM in smokers luwrr than that m
nonsmokers. but not \tatihtically
Ggnificant

No association of smoking and BM in
univariate or multivariate analysis

Controlled for age. rxc. \c\.
menopausal *It;uu\: d;tt;l lx,)
include that reported 111
Lmdqul\t t IYX I )

Controlled only tor age

Controlled for age. raw. \c'x,
weight, hut not for menopaual
status or estrogen use

Multiple te\t\ performed
controlled for apt only

Control led for age, race (white).
sex. height. weight. age ;It
menarche. menopauwl QBIU\.
numbwot chtldren hreaht
feeding. oral contracepttvr we.
phy\icul activity. and calcium
intake


TAHLE S.--Continued

P0pulat10n

I Zh po~tmenopnu~l women
volunteers ftom Sweden
randomly ;r\\ipnrd to different
estrogen dew\ and followed for
I br

X6 \homen volunttxr\ from
1 rural communities in Iowa

7X bbhitt' po\tnicnopausal
wombat not on estrogen thernpg

Bone measurement

BM by SPA at distal rudws
performed at baselme and after
I yr of estrogen treatment

BM hy SPA at distal radius

BM CT am ot the dominant
radiw at 30'~ ofdiance from
v.rist tu elbow

BM SPA at mldshaft and tltstal
radiu\

BM SPA ofm~dradiu~

Findmgs

At baseline. no difference in BM
between smokers (smoked in prior
6 mo) and non$moherr (no wokmg in
prior 6 mo): m 2X smohcr\ treated
with high dews ewogen. the mean %
increase in BM wa\ les\ than the mean
% increaw in 1X treated nonw~okrra"

No a\wciation of mokmg nnd BM

No a\wci;ltinn of wlohing and RM in
Imivarlate analy\ia

No ;IMKI~IIO~ of wohing and BM
over311 in pert- and postmenopausal
group,

No aw)ciut ion of wlohmg d BM

Comment\

No control for confounders

Small study with poor power:
hubJectb were young. limiting
generalibility: no control for
confounders

Small wdy with poor power:
no control of confounder\

Small study with poor power;
no control of confounder\

Author\ aat` that power to
detect 3 5% difference between
group, iit a= 0.05 wa5 >XO% in
buth mef~ mtl women:
confounding controlled hy
marching

c"
.J


TABLE S.--Continued

Kt?tNHICC

Ahl Kl ill.
(IYXX)

Picard ct al.
(IYXX)

Bilhrry. Wcix.
Kaplan ( I YXX 1

Slcnlelllh t'l ill.
(IYXY)

HM hq DPA of ternoral nech,
Ward\ trtanglc. trochanterlc regwn
;md 7nd4th lumbar vcrtehrur

HM hy SPA ut'did and
mdratliu\. DPA of lumbar \pine

Fintlmg\

Smoking wa a\soci;tted with Iowcr
BM in the rxiiu\ tp<O.Ol ) and of the
\pine (p4.03)

No awwiatmn ofhmohmg with etthrr
BM of the lumbar vertebrae or disral
radtu5


Eleven other published studies reported no association between smoking and bone
mineral content (Bilbrey, Weix, Kaplan 1988: Cauley et al. 1986: Johnell and Nilsson
1984; Linderglrd 1981; Lindquist 1982; Lindquist et al. 1981: McDermott and Witte
1988; Picard et al. 1988; Slemenda et al. 1987: Sowers. Wallace, Lemke 1985;
Stevenson et al. 1989). In addition. one study that found differences in bone mass
between heavy smokers and nonsmokers reported no differences in longitudinally
measured rates of bone loss (Slemenda et al. 1989). Some of these studies were small.
and the findings of no association may be due to type II statistical errors. that i<. the
failure to find a true association (Cauley et al. 1986: Slemenda et al. 1987: Sowers.
Wallace. Lemke 1985); other studies were large and had excellent statistical power
(Bilbrey. Weix, Kaplan 1988: Johnell and Nilsson 1983: Lindquist 1983: McDermott
and Witte 1988).

One study evaluated the effect of smoking on bone mass among women taking
estrogen (Jensen. Christiansen. Rodbro 1985). Among 56 postmenopausal women who
underwent replacement therapy with high doses of estrogen for I year. the mean
percentage increase in bone mass of the distal radius was I .0 I in 28 smokers compared
with 2.58 in nonsmokers. This difference was statistically significant.

Smoking as a Risk Factor for Osteoporotic Fractures

Daniel1 (1976) reported that 76 percent of women with osteoporotic vertebral
fractures smoked IO cigarettes or more per day for 5 years or more, compared with 43
percent of controls with no vertebral fracture. Smoking is strongly associated with age.
alcohol use, and, among some populations, use of exogenous estrogens. These are
potentially strong confounders of the relationship between smoking and vertebral
fracture, but Daniell's comparison between cases and controls did not consider them.

Since Daniell's 1976 study, seven other case-control studies have examined the
association between smoking and fracture of the hip or vertebrae (Table 6). Five of the
seven case<ontrol studies reported an increased risk of these osteoporotic fractures
among smokers (Aloia et al. 1985; Cooper, Barker. Wickham 1988; Paganini-Hill et
al. 1981: Seeman et al. 1983: Williamset al. 1982). and this association was statistically
significant in three of the studies (Aloia et al. 1985; Cooper, Barker, Wickham 1988:
Williams et al. 1982). In the study by Williams and coworkers (1982). smokers vvere
compared with obese nonsmokers, making it difficult to assess the independent associa-
tion of smoking with the risk of osteoporotic fractures. A second analysis of smoking
and the risk of hip or forearm fracture among the same subjects who were studied by
Williams andcolleagues (I 982) showed no overall association of smoking and fractures
(Alderman et al. 1986). In only two case<ontrol studies were statistical adjustments
made for age and exogenous estrogen use, which are potentially strong confounding
variables: in both of these studies. there was no statistically significant association of
smoking and fracture risk (Paganini-Hill et al. I98 I : Kreiger et al. 1982: Kreiger and
Hilditch 1986).

In five cohort studies (Table 7). there was no increase in the risk of fracture among
smokers (Farmer et al. 1989: Felson et al. 1988: Hemenway et al. 1988: Holbrook.
Barrett-Connor. Wingard 1988; Jensen 1986). Three of these reports were based on


TABLE 6.-Summary of case-control studies of smoking and fractures

Krferrnce


Daniel1
(iY76)

Srenian ct 31
(IYXR)

Aloia et al.
(IYX.5)

Vertebral fracture\

Population

Comparison

Estimated relattvr risk           (`omments

C&W\: 3X women aged 40 69 with
acute \ymptom:ttlc vertchrd fractures
after mm~mol trauma
Controls: 572 women outpatlcnt volunteers
aged soxw

>I0 tip/day for 3 yr vs. leaz,

4.2" h

No control for conlountlerx
no \tati\ticsl anslyv\

Caw\: 105 men aged J-l-X3 with
vertebral fracture\
Controls: I OS men aged I-LX3 with
Paget'\ diebe matched for ape and
length of ti~llowup

Nonohee. nondrinking. nonsmokers
vs. non&x. nondrinking smokers with
no underlying chv.3~:
aged <ho
aged M)MY
a&y,1 270

0.x
I .h
3.1

medid condition as\ociatcd
with hone lo\\; control\ \* ith
Paget`s disrahe may not he
representative of men unhout
vert&ral frxturex deign
controls for age. ohrslty. and
alcohol u\e

Cases: 5X white women (mca~ age 645)
volunteers with vertebral fixture
Controls 5X white women volunteerc
matched for ape

Smokers vs. nonsmokers

3.7" h

Controlled for up2 only:
multiple other ri4 factors
examined ubinf univariate tea5