Pharmacologic TX of Primary Osteoporosis or Low Bone Mass To Prevent Fxctures in Adults

CLINICAL GUIDELINE
Pharmacologic Treatment of Primary Osteoporosis or Low Bone

Mass to Prevent Fractures in Adults: A Living Clinical Guideline
From the American College of Physicians
Amir Qaseem, MD, PhD, MHA; Lauri A. Hicks, DO; Itziar Etxeandia-Ikobaltzeta, PharmD; Tatyana Shamliyan, MD, MS; and
Thomas G. Cooney, MD; for the Clinical Guidelines Committee of the American College of Physicians*
Description: This guideline updates the 2017 American females diagnosed with primary osteoporosis who have contra-
College of Physicians (ACP) recommendations on pharmaco- indications to or experience adverse effects of bisphosphonates
logic treatment of primary osteoporosis or low bone mass to (conditional recommendation; moderate-certainty evidence).
prevent fractures in adults.
Recommendation 2b: ACP suggests that clinicians use the
Methods: The ACP Clinical Guidelines Committee based RANK ligand inhibitor (denosumab) as a second-line pharmaco-
these recommendations on an updated systematic review of logic treatment to reduce the risk of fractures in males diag-
evidence and graded them using the GRADE (Grading of nosed with primary osteoporosis who have contraindications to
Recommendations Assessment, Development and Evaluation) or experience adverse effects of bisphosphonates (conditional
system. recommendation; low-certainty evidence).
Audience and Patient Population: The audience for this Recommendation 3: ACP suggests that clinicians use the
guideline includes all clinicians. The patient population includes sclerostin inhibitor (romosozumab, moderate-certainty evi-
adults with primary osteoporosis or low bone mass. dence) or recombinant PTH (teriparatide, low-certainty evi-
dence), followed by a bisphosphonate, to reduce the risk of
Recommendation 1a: ACP recommends that clinicians use fractures only in females with primary osteoporosis with very
bisphosphonates for initial pharmacologic treatment to reduce high risk of fracture (conditional recommendation).
the risk of fractures in postmenopausal females diagnosed
with primary osteoporosis (strong recommendation; high-certainty Recommendation 4: ACP suggests that clinicians take an
evidence). individualized approach regarding whether to start pharmaco-
logic treatment with a bisphosphonate in females over the age
Recommendation 1b: ACP suggests that clinicians use of 65 with low bone mass (osteopenia) to reduce the risk of frac-
bisphosphonates for initial pharmacologic treatment to reduce tures (conditional recommendation; low-certainty evidence).
the risk of fractures in males diagnosed with primary osteoporo-
sis (conditional recommendation; low-certainty evidence).
Recommendation 2a: ACP suggests that clinicians use the Ann Intern Med. 2023;176:224-238. doi:10.7326/M22-1034 Annals.org
RANK ligand inhibitor (denosumab) as a second-line pharmaco- For author, article, and disclosure information, see end of text.
logic treatment to reduce the risk of fractures in postmenopausal This article was published at Annals.org on 3 January 2023.
P rimary osteoporosis (osteoporosis that is not secondary

to a separate condition or medication) is characterized
by decreasing bone mass and density and reduced bone
Table 1, available at Annals.org) (1, 2). Fractures can
occur in any bone, but hip and spine fractures are most
common, accounting for 42% of all osteoporotic frac-
strength leading to a higher risk for fracture (Appendix tures. Fractures are associated with serious morbidity
and mortality, and people with prevalent fractures are at
much higher risk for future fractures (3–5). Overall, an esti-
See also: mated 10.2 million persons aged 50 years or older in the
Related article . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
United States have osteoporosis, and about 43.3 million
persons (>40% of older U.S. adults) have low bone mass
Summary for Patients . . . . . . . . . . . . . . . . . . . . . . . . I-24
associated with a high risk for progression to osteoporo-
Web-Only sis (6).
Supplement The clinical and economic burden of osteoporotic
fractures is increasing over time in certain racial and ethnic
* This article, written by Amir Qaseem, MD, PhD, MHA; Lauri A. Hicks, DO; Itziar Etxeandia-Ikobaltzeta, PharmD; Tatyana Shamliyan, MD, MS; and Thomas G.
Cooney, MD, was developed for the Clinical Guidelines Committee of the American College of Physicians. Individuals who served on the Clinical Guidelines
Committee from initiation of the project until its approval were Timothy J. Wilt, MD, MPH‡ (Chair); Carolyn J. Crandall, MD, MS‡ (Vice Chair); Devan Kansagara,
MD, MCR‡ (Past Vice Chair); Pelin Batur, MD, NCMP‡; Thomas G. Cooney, MD†; J. Thomas Cross Jr., MD, MPH†; Nick Fitterman, MD†; Lauri A. Hicks, DO†;
Jennifer S. Lin, MD, MCR†; Michael Maroto, JD, MBA†§; Reem A. Mustafa, MD, PhD, MPH‡; Adam J. Obley, MD†; Douglas K. Owens, MD, MS‡; Jeffrey A. Tice,
MD†; Janice E. Tufte†§; Sandeep Vijan, MD, MS‡; and John W. Williams Jr., MD, MHS‡. Kate Carroll, MPH, was a nonauthor contributor from ACP staff.
Approved by the ACP Board of Regents on 25 April 2022.
† Author.
‡ Nonauthor contributor.
§ Nonphysician public representative.
224 © 2023 American College of Physicians
Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass in Adults CLINICAL GUIDELINE
groups compared with White Americans, although differ- or failure or intolerability of osteoporosis medications rather
ences in treatment effects for these populations remain than scores from available tools (35–39). The recommenda-
unclear (7). Over the past decade, the prevalence of osteo- tions are based on biological sex assigned at birth because
porosis in the United States increased in females but not most studies reported sex rather than gender and the major-
males (6, 8). However, males with osteoporotic hip fractures ity enrolled only older females.
have greater morbidity and mortality than females with hip
fractures and receive treatments aimed at fracture preven-
tion less often than females (9–12). There is substantial bur- INTENDED AUDIENCE
den for working patients due to absenteeism and loss of The intended audience is all clinicians. The manage-
productivity (13–15). ment of secondary osteoporosis in people with cancer
The American College of Physicians (ACP) has previ- (40–43) and other serious illnesses is outside the scope
ously published clinical recommendations on screening of this guideline.
and pharmacologic interventions for osteoporosis (16,
17), with the most recent guideline, published in 2017,
aimed at treatment of osteoporosis (18). GUIDELINE DEVELOPMENT PROCESS
The CGC developed this guideline according to ACP's
SCOPE AND PURPOSE guideline development process (44) and its policy on disclo-
sure of interests and management of conflicts of interest (45).
The purpose of this ACP guideline is to present a
focused update on clinical recommendations for phar- The CGC used Evidence-to-Decision tables when reporting
macologic treatments (Table) of osteoporosis and low the evidence (Supplement Appendixes 1 to 3, available
bone mass to prevent fractures in adults, based on the at Annals.org) and graded the recommendations using
best available evidence of the benefits and harms of treat- the GRADE (Grading of Recommendations Assessment,
ments and consideration of patient values, preferences, Development and Evaluation) approach (Appendix Figure,
and costs (Figures 1 to 3). Since publication of the 2017 available at Annals.org) (46). Supplement Appendix 4
ACP guideline (18), evidence has emerged on the effi- (available at Annals.org) presents baseline patient char-
cacy of human parathyroid hormone–related peptides acteristics, and Supplement Appendix 5 (available at
(24, 25), sclerostin inhibitors (26, 27), the comparative Annals.org) lists the key questions for the supporting
effectiveness of treatments (28–30), and treatments in systematic review and details about the methods for the
males. This update also adds key questions on values and guideline and systematic review. ACP completes a Guidelines
preferences and costs of interventions and incorporates International Network (GIN) standards reporting form for
network meta-analysis. The update of the evidence regard- each guideline it publishes, which can be found in GIN's
ing use of estrogen, treatment duration, drug discontinua- International Guideline Library or on ACP's website (www.
tion (31), and serial bone mineral density monitoring (32) acponline.org/clinical-information/guidelines/guideline-
was not addressed in this update but will be reevaluated process).
by the Clinical Guidelines Committee (CGC) during the liv- Because there are many ongoing studies (Table 5c
ing review process. of Supplement Appendix 5), the CGC is planning to main-
We evaluated the following pharmacologic interven- tain this topic as a living guideline with quarterly literature
tions: an analogue of human parathyroid hormone–related surveillance and periodic updating of the systematic review
protein (PTHrP) (abaloparatide), bisphosphonates (alen- and the clinical recommendations. The CGC will consider
dronate, ibandronate, risedronate, zoledronate), a recep- quantitative and qualitative factors, such as the certainty of
tor activator of nuclear factor κB (RANK) ligand inhibitor the evidence, the balance between benefits and harms,
(denosumab), recombinant human parathyroid hormone and contextual considerations to assess whether the new
(recombinant PTH) (teriparatide), a sclerostin inhibitor evidence may lead to changes to the recommendations
(romosozumab), and selective estrogen receptor modula- and the need for an update. The CGC may decide to retire
tors (SERMs) (bazedoxifene, raloxifene). Appendix Table 2 the topic from living status if it is no longer considered a
(available at Annals.org) summarizes definitions of fracture priority for decision making, when there is confidence that
outcomes, and the Table provides an overview of medica- conclusions are not likely to change with new evidence, or
tions licensed in the United States for treatment of osteo- if it becomes unlikely that new evidence will emerge (47).
porosis. We focused on effectiveness and harms of active
drugs compared with placebo or bisphosphonates.
SYSTEMATIC REVIEW AND SUMMARY OF FINDINGS
POPULATION This guideline is based on an accompanying system-
The population is adults (premenopausal and post- atic review and network meta-analysis completed by the
menopausal females and males) with low bone mass (33) ACP Center for Evidence Reviews at the Portland Veterans
or primary osteoporosis as diagnosed in primary studies Affairs Research Foundation and funded by ACP. The
(34). In assessing baseline risk for fracture, we consider accompanying systematic review and the Supplement
diagnosis of osteoporosis, history of osteoporotic frac- Appendixes provide the appraised evidence of benefits
tures (clinical or incidental), multiple risk factors for fractures, and harms of evaluated pharmacologic interventions (34).
Annals.org Annals of Internal Medicine • Vol. 176 No. 2 • February 2023 225

CLINICAL GUIDELINE Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass in Adults
Table. Medications Licensed in the United States for Treatment of Osteoporosis

Drug Name (Class) Route; Frequency Types of Fractures Examined in Randomized Average Annual FDA Warning
Clinical Trials at Long-Term Follow-up (>36 mo) Medicare Spending Per
Beneficiary in 2019
Hip Clinical Any Radiographic
Vertebral Clinical Vertebral
Antiresorptive drugs
Alendronate (bisphosphonate)*†‡ By mouth (tablet or solu- Yes No Yes Yes $793–$1306 (brand- Upper gastrointestinal irritation;
tion); once a day name); $39 (generic) osteonecrosis of the jaw; atypical
(10 mg) or once a femur fractures; severe bone,
week (70 mg)§ joint, and muscle pain
Risedronate (bisphosphonate)*†‡ By mouth; once a day, Yes No No Yes $2036–$2732 (brand- Upper gastrointestinal irritation;
once a week, or 2 d in name); $604 (generic) osteonecrosis of the jaw; atypical
a row once per femur fractures; severe bone,
month§ joint, and muscle pain
Ibandronate (bisphosphonate)*‡ By mouth; once a No No No Yes $1379 (brand-name); Upper gastrointestinal irritation;
month§ $220 (generic) osteonecrosis of the jaw; atypical
femur fractures; severe bone,
joint, and muscle pain
Zoledronate (bisphosphonate)*†‡ Intravenous; once a Yes Yes Yes Yes $855 (brand-name); Osteonecrosis of the jaw; atypical
year§ $316–$987 (generic) femur fractures; severe bone,
joint, and muscle pain
Denosumab (RANK ligand By injection (subcutane- Yes Yes Yes Yes $1913–$12 241 (brand- Dermatologic reactions and serious
inhibitor)†|| ous); every 6 mo¶ name) infection, including skin infec-
tions; suppression of bone turn-
over contributing to adverse
outcomes, such as osteonecrosis
of the jaw, atypical fractures, and
delayed fracture healing
Anabolic drugs
Abaloparatide (parathyroid By injection (subcutane- No No Yes** Yes** $9873 (brand-name) Hereditary osteosarcoma
hormone–related protein)|| ous); once a day disorders††
Teriparatide (recombinant By injection (subcutane- Yes** Yes** Yes** Yes** $22 156 (brand-name) Hereditary osteosarcoma
human parathyroid ous); once a day disorders††
hormone)||‡‡
Romosozumab (sclerostin By injection (subcutane- No Yes** Yes** Yes** $5574 (brand-name) Cardiovascular risk
inhibitor)|| ous); once a month Stroke history or risk||||
for 12 mo§§
Estrogen agonist on bones

Raloxifene (selective estrogen By mouth; once a day Yes Yes Yes Yes $1730 (brand-name); Stroke history or risk
receptor modulator)*‡ $593 (generic) Thromboembolism history or risk¶¶
FDA = U.S. Food and Drug Administration; RANK = receptor activator of nuclear factor κB.
* Indicated for treatment of osteoporosis in postmenopausal females.
† Indicated for males. Bisphosphonates have been approved for males with primary osteoporosis based on improvement in bone mineral density,
and denosumab is approved for males with secondary osteoporosis based on a reduction in risk for vertebral fractures (19).
‡ Indicated for the prevention of osteoporosis in postmenopausal females with low bone mass.
§ All patients receiving bisphosphonate therapy should have the need for continued therapy reevaluated periodically. Patients at low risk for fracture should
be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture reevaluated periodically.
|| Indicated for postmenopausal females with osteoporosis who are at high risk for fracture, defined as a history of osteoporotic fracture or multiple
risk factors for fracture or patients who have failed or are intolerant to other available osteoporosis therapy.
¶ Denosumab discontinuation is associated with multiple vertebral fractures in some patients (20).
** Short-term follow-up (12 to 36 months).
†† Dose-dependent increase in incidence of osteosarcoma in preclinical studies.
‡‡ Indicated for males; increase in bone mass in males with primary or hypogonadal osteoporosis who are at high risk for fracture.
§§ Use of romosozumab should be limited to 12 monthly doses because the anabolic effect wanes after 12 monthly doses (21).
|||| The analysis of the FDA Adverse Event Reporting System suggested higher risk for major adverse cardiovascular events associated with romosozumab
(22). The current FDA safety warnings recommend avoiding use of romosozumab in patients with high risk for major cardiovascular events (21).
¶¶ Higher risk for venous thromboembolism and fatal stroke in females who have documented coronary heart disease or are at increased risk for
major coronary events (23).
OUTCOMES OF INTEREST benefits of the various treatments, we looked at fracture rates

Benefits and Harms at longer time (≥36 months) and shorter time (12 to <36
Critical outcomes that were evaluated included months) to outcome assessment (48). The CGC prioritized
patient-oriented clinical outcomes of fractures (Appendix benefits and harms that lasted at least 36 months over those
Table 2), patient functional status, quality of life, and serious only assessed at 12 to less than 36 months (34).
adverse events, and important outcomes included with- Each study contributed to outcomes at 1 time point
drawals due to adverse events. When evaluating the net of fracture assessment (12 to <36 months or ≥36 months). In
226 Annals of Internal Medicine • Vol. 176 No. 2 • February 2023 Annals.org

Figure 1. Treatments to reduce fractures in postmenopausal females with primary osteoporosis.
Treatments to Reduce Fractures in Postmenopausal Females

With Primary Osteoporosis
Recommendations
RECOMMENDATION: ACP recommends that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of
fractures in postmenopausal females diagnosed with primary osteoporosis (strong recommendation; high-certainty evidence).
RECOMMENDATION: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment
to reduce the risk of fractures in postmenopausal females diagnosed with primary osteoporosis who have contraindications to or
experience adverse effects of bisphosphonates (conditional recommendation; moderate-certainty evidence).
RECOMMENDATION: ACP suggests that clinicians use the sclerostin inhibitor (romosozumab, moderate-certainty evidence) or
recombinant PTH (teriparatide; low-certainty evidence), followed by a bisphosphonate, to reduce the risk of fractures only in females
with primary osteoporosis with very high risk of fracture (conditional recommendation).
RATIONALE: Bisphosphonates had the most favorable balance among benefits, harms, patient values and preferences, and cost among
the examined drugs in postmenopausal females with primary osteoporosis and should be used as first-line treatment. Denosumab also
had a favorable long-term net benefit, but bisphosphonates are much cheaper than other pharmacologic treatments and available in
generic formulations. Evidence showed that the benefits of recombinant PTH (teriparatide) or the sclerostin inhibitor (romosozumab) may
have outweighed harms compared with placebo in a select population of postmenopausal females (mean age >74 years) with osteoporosis
and very high risk for fracture. Bisphosphonates were associated with higher risk for osteonecrosis of the jaw and atypical femoral fractures.
Teriparatide may have resulted in no difference in risk for serious adverse events but probably increased the risk for withdrawal due to
adverse events in RCTs after 36 months.
Patient Population
Postmenopausal females diagnosed with primary osteoporosis
Interventions Compared With Placebo
Bisphosphonates (alendronate, risedronate, zoledronate), denosumab, teriparatide, abaloparatide, romosozumab, raloxifene
Key Outcomes Assessed at 12–36 and ≥36 Months
Hip fracture, any clinical and clinical vertebral fractures, radiographic vertebral fractures, harms (serious adverse effects and
treatment withdrawal due to adverse effects)
Key Outcomes
Hip Fractures, ≥36 Months Clinical Vertebral Fracture, ≥36 Months

CERTAINTY OF
–50 per 1000 treated patients 0 CERTAINTY OF –50 per 1000 treated patients 0 THE EVIDENCE
THE EVIDENCE
BISPHOSPHONATES HIGH
BISPHOSPHONATES 6 fewer MODERATE 18 fewer
VS. PLACEBO
VS. PLACEBO
DENOSUMAB HIGH
DENOSUMAB 16 fewer
4 fewer MODERATE VS. PLACEBO
VS. PLACEBO
Raloxifene may not differ from placebo (low-certainty evidence). Evidence is Raloxifene probably does not differ from placebo (moderate-certainty
not available for other treatments. evidence). Evidence is not available for other treatments.
Hip Fractures, 12–36 Months Clinical Vertebral Fracture, 12–36 Months

CERTAINTY OF
–50 per 1000 treated patients 0 CERTAINTY OF –100 per 1000 treated patients 0 THE EVIDENCE
THE EVIDENCE
BISPHOSPHONATES
BISPHOSPHONATES 21 fewer HIGH
8 fewer HIGH VS. PLACEBO
VS. PLACEBO
SEQUENTIAL THERAPY ROMOSOZUMAB
4 fewer MODERATE
OF ROMOSOZUMAB VS. PLACEBO
12 fewer MODERATE
TO ALENDRONATE VS.
ALENDRONATE ALONE TERIPARATIDE
45 fewer LOW
Teriparatide may not differ from placebo (low-certainty evidence). Evidence is VS. PLACEBO
not available for other treatments.
RALOXIFENE VS.
35 fewer LOW
PLACEBO
Withdrawal Due to Adverse Events, ≥36 Months SEQUENTIAL THERAPY

OF ROMOSOZUMAB 13 fewer MODERATE
0 per 1000 treated patients 150 CERTAINTY OF TO ALENDRONATE VS.
THE EVIDENCE ALENDRONATE ALONE
TERIPARATIDE VS. Evidence is very uncertain (insufficient) about the effect of denosumab.
127 more MODERATE
PLACEBO Evidence is not available for other treatments.
Continued on following page
ACP = American College of Physicians; PTH = parathyroid hormone; RANK = receptor activator of nuclear factor κB; RCT = randomized controlled trial.

Figure 1–Continued
Serious Adverse Events, ≥36 Months

CERTAINTY OF
THE EVIDENCE
Bisphosphonates and denosumab resulted in no differences in serious adverse events and withdrawals due to adverse HIGH to
events in RCTs. MODERATE
Bisphosphonates were associated with higher risk for osteonecrosis of the jaw and atypical femoral or subtrochanteric LOW
fractures in observational studies, with higher risk after longer treatment duration.
Romosozumab followed by alendronate probably did not increase risk for serious harms or withdrawal due to adverse MODERATE to
effects compared with bisphosphonate alone at 12- to 36-month outcome assessment in an RCT. LOW
Teriparatide may have resulted in no difference in risk for serious adverse events but probably increased the risk for LOW to
withdrawal due to adverse events in RCTs. MODERATE
Clinical Considerations
Clinicians should prescribe generic medications if possible rather than more expensive brand-name medications.
Clinicians treating postmenopausal females with osteoporosis should encourage adherence to recommended drug treatments and
healthy lifestyle modifications, including exercise, and counseling for evaluation and prevention of falls.
Adequate calcium and vitamin D intake should be part of fracture prevention in all postmenopausal females with low bone mass or
osteoporosis.
Clinicians should assess baseline risk for fracture based on individualized assessment of bone density, history of fractures, response to
prior treatments for osteoporosis, and multiple risk factors for fractures in postmenopausal females with primary osteoporosis.
Current evidence suggests that increasing the duration of bisphosphonate therapy to longer than 5 years probably reduced risk for new vertebral
fractures but not risk for other fractures at the expense of increased risk for long-term harms. Therefore, clinicians should consider stopping
bisphosphonate treatment after 5 years unless the patient has a strong indication for treatment continuation.
The decision of a temporary treatment discontinuation (holidays) should be individualized and based on baseline risk for fractures, type of
medication and its half-life in bone, duration of discontinuation, benefits and harms of discontinuation, and higher risk for fracture due to
drug discontinuation.
Females initially treated with an anabolic agent should be offered an antiresorptive agent after discontinuation to preserve gains and because of
serious risk for rebound and multiple vertebral fractures.
Older postmenopausal females with primary osteoporosis who are at increased risk for falls and other adverse events due to polypharmacy or
drug interactions need individualized treatment selection based on comorbidities and concomitant medications associated with higher risk for
falls/fractures.
addition, we prioritized prevention of hip fractures and clini- Treatments to Reduce Fractures in Adults
cal vertebral fractures followed by prevention of any clinical Diagnosed With Osteoporosis
or radiographic vertebral fractures based on the high risk for Recommendation 1a: ACP recommends that clinicians
disability, institutionalization, morbidity, and mortality in peo- use bisphosphonates for initial pharmacologic treatment to
ple with clinical fractures (3, 4) and the high risk for future reduce the risk of fractures in postmenopausal females diag-
fractures in people with radiographic fractures (49). We also nosed with primary osteoporosis (strong recommendation;
prioritized serious adverse events reported in randomized high-certainty evidence).
controlled trials (RCTs) and observational studies as more Recommendation 1b: ACP suggests that clinicians
clinically important than withdrawals due to adverse events, use bisphosphonates for initial pharmacologic treatment
which were usually available only from RCTs. Overall, we to reduce the risk of fractures in males diagnosed with
contextualized the balance between benefits and harms primary osteoporosis (conditional recommendation; low-
based on the direction and magnitude of treatment effects certainty evidence).
across all outcomes and the certainty of evidence. Recommendation 2a: ACP suggests that clinicians
use the RANK ligand inhibitor (denosumab) as a second-
Public and Patient Values and Preferences
line pharmacologic treatment to reduce the risk of frac-
The CGC considered values and preferences of
tures in postmenopausal females diagnosed with primary
the public and patients when assessing the value of the
osteoporosis who have contraindications to or experi-
interventions.
ence adverse effects of bisphosphonates (conditional rec-
Costs ommendation; moderate-certainty evidence).
The CGC considered costs and burden of care when Recommendation 2b: ACP suggests that clinicians use
assessing the value of the interventions. the RANK ligand inhibitor (denosumab) as a second-line
pharmacologic treatment to reduce the risk of fractures in
males diagnosed with primary osteoporosis who have contra-
RECOMMENDATIONS indications to or experience adverse effects of bisphospho-
Figures 1 to 3 summarize the recommendations. nates (conditional recommendation; low-certainty evidence).

Figure 2. Treatments to reduce fractures in males with primary osteoporosis.
Treatments to Reduce Fractures in Males With Primary Osteoporosis
Recommendations
RECOMMENDATION: ACP suggests that clinicians use bisphosphonates for initial pharmacologic treatment to reduce the risk of fractures
in males diagnosed with primary osteoporosis (conditional recommendation; low-certainty evidence).
RECOMMENDATION: ACP suggests that clinicians use the RANK ligand inhibitor (denosumab) as a second-line pharmacologic treatment
to reduce the risk of fractures in males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects
of bisphosphonates (conditional recommendation; low-certainty evidence).
RATIONALE: There was no evidence suggesting differences in treatment benefits and harms by sex. Bisphosphonates are approved for
males with primary osteoporosis based on improvement in bone mineral density, and denosumab is approved for males with secondary
osteoporosis based on the reduction in the risk for vertebral fractures. Limited evidence was available for the effect of bisphosphonates
on radiographic vertebral fracture prevention in males with primary osteoporosis. Hence, we complemented low-certainty conclusions of
the effect of bisphosphonate treatment for males by extrapolating results from trials including females in order to recommend the same
first- and second-line treatments for both males and females. We downgraded the overall certainty of evidence from the available data in
females to low due to indirectness, and we downgraded the strength of the recommendation to conditional.
Patient Population
Males diagnosed with primary osteoporosis
Interventions Compared With Placebo
Bisphosphonates (alendronate, risedronate, zoledronate), denosumab, teriparatide, abaloparatide, romosozumab
Hip fracture, any clinical and clinical vertebral fractures, radiographic vertebral fractures, harms (serious adverse effects and
treatment withdrawal due to adverse effects)
Key Outcomes
Radiographic Vertebral Fractures, ≥36 Months

–150 per 1000 treated patients 0 CERTAINTY OF
THE EVIDENCE
BISPHOSPHONATES
140 fewer LOW
VS. PLACEBO
CERTAINTY OF
THE EVIDENCE
Bisphosphonates probably reduced radiographic vertebral fractures, but not any clinical fractures, at 12–36 months. MODERATE
No RCTs evaluated hip fractures after bisphosphonates. Other treatments aimed at fracture prevention have not been
examined yet in males with primary osteoporosis.
Bisphosphonates resulted in no differences in the risk for serious adverse events in RCTs assessing harms at HIGH
12–36 months.
Bisphosphonates probably resulted in no differences in withdrawal due to adverse events in RCTs assessing harms MODERATE
at 12–36 months.
Bisphosphonates probably resulted in no differences in the risk for atrial fibrillation in RCTs assessing harms at LOW
12–36 months.
ACP = American College of Physicians; RANK = receptor activator of nuclear factor κB; RCT = randomized controlled trial.
Rationale were associated with higher risk for osteonecrosis of the jaw
Bisphosphonates should be used as first-line treat- and atypical femoral or subtrochanteric fractures in observa-
ment in both females and males with primary osteoporosis. tional studies compared with people with osteoporosis who
In postmenopausal females and males with osteoporosis, were not treated with bisphosphonates (low certainty of evi-
bisphosphonates had the most favorable balance among dence) (Tables 1b.i to 1b.iii of Supplement Appendix 1) (34).
benefits, harms, patient values and preferences, and cost In addition to net clinical benefits, bisphosphonates are
among the drug classes we evaluated (Tables 1a to 1c of much cheaper (Table) than other pharmacologic treat-
Supplement Appendix 1) (34). However, bisphosphonates ments and are available in generic formulations.

Figure 3. Treatments to reduce fractures in postmenopausal females with low bone mass.
Treatments to Reduce Fractures in Postmenopausal Females

With Low Bone Mass
Recommendations
RECOMMENDATION: ACP suggests that clinicians take an individualized approach regarding whether to start pharmacologic treatment
with a bisphosphonate in females over the age of 65 with low bone mass (osteopenia) to reduce the risk of fractures (conditional
recommendation; low-certainty evidence).
RATIONALE: Evidence suggested that any benefits of using a bisphosphonate to reduce the risk for fracture in females with low bone
mass need to be balanced with harms and costs based on an individualized assessment of the baseline risk for fracture.
Patient Population
Postmenopausal females diagnosed with low bone mass
Interventions Compared With Placebo or Each Other
Bisphosphonates (alendronate, risedronate, zoledronate)
Denosumab
Teriparatide
Abaloparatide
Romosozumab
Raloxifene
Hip fracture
Any clinical and clinical vertebral fractures
Radiographic vertebral fractures
Harms (serious adverse effects and treatment withdrawal due to adverse effects)
Key Outcomes
Overall, Long-Term
CERTAINTY OF
THE EVIDENCE
Zoledronate may have reduced the risk for any clinical or vertebral fractures at 6 years of treatment without LOW
higher risk for serious adverse events compared with placebo in a randomized controlled clinical trial.
The evidence is very uncertain about the effect of bisphosphonates (zoledronate) on the risk for hip fractures, INSUFFICIENT
withdrawal due to adverse events, and atrial fibrillation at 6 years (insufficient).
Other medications have not been examined yet in females with low bone mass.
ACP = American College of Physicians.
These recommendations are applicable to bisphospho- Benefits and Harms of Bisphosphonates

nates studied in the eligible primary RCTs (alendronate, Evidence from the network meta-analysis suggested
risedronate, or zoledronate), which were evaluated in the no greater benefits from other drug classes compared with
accompanying evidence review (34). There is no evidence bisphosphonates (Table 2a of Supplement Appendix 2)
that ibandronate reduces hip fractures (34). The RANK ligand (34). High-certainty evidence showed that bisphosphonates
inhibitor (denosumab) can be used as a second-line treat- reduced risk for hip fractures (absolute risk difference [ARD],
ment in both females and males at high risk for fracture. 6 fewer events per 1000 patients), clinical vertebral fractures
Evidence from RCTs showed that denosumab had a (ARD, 18 fewer events per 1000 patients), any clinical fracture
favorable long-term net benefit in postmenopausal females (ARD, 24 fewer events per 1000 patients), and radiographic
with primary osteoporosis, a history of osteoporotic fractures, vertebral fractures (ARD, 56 fewer events per 1000 patients)
and a history of treatment with bisphosphonates (Table 4a compared with placebo in RCTs assessing outcomes at least
of Supplement Appendix 4) (34). Use of denosumab was 36 months after treatment initiation (Table 1a of Supplement
not associated with a higher risk for osteonecrosis of the Appendix 1). High-certainty evidence showed no differences
jaw (34); however, events were detected in the extension between bisphosphonates and placebo in serious adverse
trials and more data are needed to clarify the risk. events and withdrawals due to adverse events at least 3

years after initiation of treatment in included RCTs (Table 1a phonate treatment for males by extrapolating results from tri-
of Supplement Appendix 1) (34). However, evidence from als that included females in order to recommend the same
observational studies showed that bisphosphonates were first- and second-line treatments for males and females.
associated with higher risk for atypical femoral fractures and We downgraded the overall certainty of evidence from the
osteonecrosis of the jaw (pooled from 5 observational stud- available data in females to low due to indirectness, and
ies; adjusted risk ratio, 3.4 [95% CI, 1.9 to 5.2]; low certainty) we downgraded the strength of the recommendation to
at least 2 to 3 years after treatment initiation compared with conditional.
people with osteoporosis who were not treated with bisphos- The systematic review identified 10 studies (6 RCTs
phonates (Tables 1b.i to 1b.iii of Supplement Appendix 1), and 4 observational studies) that included only males
with osteoporosis or patients stratified by sex (34). Low-
although observed events were uncommon (unadjusted
certainty evidence showed that bisphosphonates may
incidence of osteonecrosis of the jaw was 0.01% to 0.3%
have reduced radiographic vertebral fractures (ARD, 140
of bisphosphonate users) (34). Longer treatment dura-
fewer events per 1000 patients) compared with placebo
tion with bisphosphonates may have been associated in RCTs assessing outcomes at least 36 months from
with higher risk for osteonecrosis of the jaw (34) and treatment initiation in males (Table 1c of Supplement
atypical femoral fractures (34). Higher risk for atypical Appendix 1). No RCTs evaluated hip fractures. Bis-
femoral fractures was observed in Asian females com- phosphonates probably reduced radiographic vertebral
pared with non-Hispanic White females (595 vs. 109 per but not any clinical fractures at 12 to less than 36 months
100 000 person-years) (34). (moderate certainty) (34). Evidence from RCTs assessing
Compared with other medications, evidence from harms at 12 to less than 36 months showed no differences
RCTs suggested that there may be no differences between in the risk for serious adverse events (high certainty) and
bisphosphonates and denosumab in fracture risk reduction probably no difference in withdrawals due to adverse
at 36 months or beyond (low certainty; Table 2a of events (moderate certainty) and atrial fibrillation (low cer-
Supplement Appendix 2). Raloxifene probably reduced radi- tainty) in males (Table 1c of Supplement Appendix 1) (34).
ographic fractures compared with placebo but increased Longer treatment with bisphosphonates was associated
risk for withdrawal due to adverse events in RCTs and was with higher risk for atypical femoral fractures and osteo-
associated with higher risk for venous thromboembolism in necrosis of the jaw (34). For other harms, zoledronate
RCTs (34). Evidence from studies with shorter follow-up increased the likelihood of pyrexia, myalgia, and arthral-
(12 to <36 months) showed no greater net benefit from gia (50–52).
other drug classes compared with bisphos-phonates (Tables
2a and 2b of Supplement Appendix 2) (34). Applicability
Most studies enrolled adults at high risk for fracture,
Benefits and Harms of the RANK Ligand Inhibitor although definitions of baseline risk were heterogeneous
(Denosumab) due to different scoring scales used in the RCTs and dif-
Currently, denosumab is the only available RANK ligand ferent proportions of adults with prior vertebral fractures
inhibitor. Evidence showed that denosumab reduced clinical at baseline (Table 4a of Supplement Appendix 4) (34).
vertebral fractures (ARD, 16 fewer events per 1000 patients; Appendix Table 3 (available at Annals.org) summarizes
high certainty) and probably reduced risk for hip fractures risk factors for fractures (36–39). Primary studies did not
(ARD, 4 fewer events per 1000 patients; moderate certainty), consistently report on prior treatment response, although
any clinical fracture (ARD, 14 fewer events per 1000 patients; most allowed previous treatments with bisphosphonates
moderate certainty), and radiographic vertebral fractures (Table 4a of Supplement Appendix 4) (34). Only bisphos-
(ARD, 48 fewer events per 1000 patients; moderate cer- phonates have been tested as first-line treatment in treatment-
tainty) in RCTs assessing outcomes at least 3 years after naive patients (34). Primary studies enrolled adults with
treatment initiation (Table 1a of Supplement Appendix 1). osteoporosis who were already taking vitamin D, calcium, or
Denosumab probably reduced risk for radiographic verte- both supplements (Table 4a of Supplement Appendix 4)
bral fractures at shorter follow-up (12 to <36 months) (ARD, (34). Most studies included females and a very small number
64 fewer events per 1000 patients; moderate certainty) of males with primary osteoporosis (Table 4b of Supplement
(Table 1a of Supplement Appendix 1). Appendix 4), but few RCTs assessed the effect of zoledronate
Evidence from RCTs showed there are probably no in males with osteoporosis (34).
differences in serious adverse effects and withdrawal
due to adverse effects at 36 months between denosumab Values and Preferences
and placebo (moderate certainty; Table 1a of Supplement Limited evidence on values and preferences related
Appendix 1). to net benefit from oral or injectable medications (34, 53,
54) showed that females considered the effectiveness
Treatment in Males and adverse effects of treatments equally, followed by
There was no evidence suggesting differences in convenience of taking the medication and effect on daily
treatment benefits and harms by sex (34). Evidence was routine (they preferred less frequent dosing, oral route
limited on the effect of bisphosphonates and fracture of administration, and injectable route over oral if taken
prevention in males with primary osteoporosis (Table 1c at a lower frequency) (34). Out-of-pocket costs were con-
of Supplement Appendix 1) (34). Therefore, we comple- sidered extremely important factors (34). Bisphosphonates
mented low-certainty conclusions of the effect of bisphos- can be taken through various routes and at various

frequencies, giving patients an opportunity to tailor treat- harms only in a select population of postmenopausal
ment to their preferences (Table). Views from the CGC females (mean age, >74 years) with osteoporosis and very
Public Panel reported preferences for use of bisphospho- high risk for fracture ( Table 1a of Supplement Appendix
nates to treat osteoporosis. Similar to the research evi- 1 and Table 2a of Supplement Appendix 2) (34, 60–65).
dence, the Public Panel's preferences were also driven by We developed our recommendations on the basis of the
the profile of benefits and harms. assessment of very high risk for fracture in primary RCTs
(60, 65). Very high risk was based on older age, a recent
Costs
fracture (for example, within the past 12 months), history of
We considered national data on resource use and
multiple clinical osteoporotic fractures, multiple risk factors for
published systematic reviews of economic analyses of
fracture (see Appendix Table 3), or failure of other available
lifetime horizon cost applicable to the United States (55).
osteoporosis therapy (30, 66–68) (Table 4a of Supplement
National Medicare data suggested that bisphosphonates
Appendix 4).
are substantially less expensive than the other drug classes
Currently, romosozumab is the only available sclerostin
(Table 1d and Figures 1b and 1c of Supplement Appendix
inhibitor and teriparatide is the only available recombinant
1). Medicare data also showed that generic bisphospho-
PTH. Discontinuation of romosozumab or teriparatide treat-
nates (oral alendronate or intravenous zoledronate) were the
ment may result in rapid bone loss and higher fracture risk
least expensive compared with brand-name formulations
and should be followed by administration of an antiresorp-
(Table 1e of Supplement Appendix 1). The overall treatment
tive agent (69, 70).
cost was probably higher for injectable intravenous formula- Because this is a conditional recommendation for
tions because it included reimbursement for clinic visits, infu- females, we did not make a recommendation for males
sion costs (intravenous), and potential missed work hours for because any further downgrading due to indirectness
working patients. Systematic reviews concluded that the was not sufficient to support a clinical recommendation.
most cost-effective initial therapy for postmenopausal osteo-
porosis was generic zoledronate or oral alendronate (Table Benefits and Harms of Recombinant PTH (Teriparatide)
1f of Supplement Appendix 1) (34, 56) and that the maxi- None of the included studies evaluated the long-
mum net benefit from bisphosphonates is observed in term benefits of teriparatide (Table 1a of Supplement
patients with high baseline risk for fractures (Table 1g of Appendix 1). Evidence showed that teriparatide reduced
Supplement Appendix 1) (34). These analyses did not risk for any clinical fractures and radiographic vertebral frac-
address poor adherence to oral bisphosphonates or addi- tures (ARD, 27 and 69 fewer events per 1000 patients,
tional costs associated with injectable drugs or brand- respectively; high certainty) and may have reduced clinical
name formulations. The absolute cost to use denosumab, vertebral fractures (ARD, 45 fewer events per 1000 patients;
romosozumab, or teriparatide is higher because discontin-
low certainty) compared with placebo at 24-month outcome
uation should be followed by an alternative sequential
assessment (34) but may have resulted in no difference in
treatment to prevent rebound fractures.
Evidence from the published cost-effectiveness analysis risk for hip fractures (low certainty). Evidence from RCTs
(CEA) was insufficient to conclude economic value of drugs showed that teriparatide may have resulted in no difference
for osteoporosis (34). The most recent systematic review of in risk for serious adverse effects (low certainty) but probably
CEAs of osteoporosis drugs included 12 CEAs, but only 1 increased risk for withdrawal due to adverse effects at 36-
was from the United States (57). The review suggested that and 24-month follow-up (ARD, 127 and 17 more events per
baseline risk for fracture, the magnitude of medication effects
1000 patients, respectively; moderate certainty), most com-
on fracture prevention, medication adherence and persist-
ence, and drug cost contributed to cost-effectiveness of monly due to nausea, dizziness, vomiting, headache, palpita-
available medications (58). A single CEA conducted in the tions, and leg cramps (34, 71).
United States (57) concluded that denosumab was cost- Compared with bisphosphonates at 24-month out-
effective compared with other osteoporosis treatments in come assessment, evidence showed that teriparatide
older U.S. males with osteoporosis, based on indirect evi- probably reduced risk for radiographic vertebral frac-
dence from a single RCT in postmenopausal females (59). tures (ARD, 66 fewer events per 1000 patients; moderate
Recommendation 3: ACP suggests that clinicians certainty), may have reduced risk for any clinical fracture
use the sclerostin inhibitor (romosozumab, moderate- (ARD, 46 fewer events per 1000 patients; low certainty),
certainty evidence) or recombinant PTH (teriparatide, and may have resulted in no differences in serious
low-certainty evidence), followed by a bisphosphonate, adverse events (low certainty) or withdrawal due to
to reduce the risk of fractures only in females with pri-
adverse events (moderate certainty). However, teripara-
mary osteoporosis with very high risk of fracture (condi-
tional recommendation). tide increased risk for withdrawal due to adverse events
in the longer term (36 months) (risk ratio, 3.1; low cer-
Rationale tainty) (Table 2a of Supplement Appendix 2) (34). There
Evidence showed that the benefits after 24 months is not yet sufficient evidence on the benefits and harms
of treatment with recombinant PTH (teriparatide) or the of sequential therapy with bisphosphonates after 72
sclerostin inhibitor (romosozumab) may have outweighed weeks of teriparatide (34, 72).

Benefits and Harms of the Sclerostin Inhibitor did not make a recommendation for males because any fur-
(Romosozumab) ther downgrading due to indirectness was not sufficient to
None of the included studies evaluated the long-term support a clinical recommendation.
benefits and harms of romosozumab or reported its effect
on risk for hip fractures (34). Moderate-certainty evidence Values and Preferences
from RCTs assessing outcomes at 12 to 36 months after The systematic review did not identify any studies of
treatment initiation showed that romosozumab probably patient values and preferences in adults treated with
reduced clinical vertebral fractures (ARD, 4 fewer events romosozumab or teriparatide (34).
per 1000 patients), radiographic vertebral fractures (ARD,
Costs
13 fewer events per 1000 patients), and any clinical Teriparatide is the most expensive of the reviewed
fractures (ARD, 9 fewer events per 1000 patients) com- treatments, with an average annual cost per Medicare ben-
pared with placebo, but prevention of hip fractures was eficiary of $22 156. Romosozumab is more expensive than
not reported (Table 1a of Supplement Appendix 1) (34). bisphosphonates (average annual cost per Medicare bene-
At 12 months, romosozumab compared with bisphospho- ficiary is $5574 vs. a range of $39 to $2700) but may be
nates may have resulted in no differences in clinical or less expensive than denosumab (range of $1913 to
radiographic vertebral fractures (low certainty) with no $12 241) (Figure 1c of Supplement Appendix 1). The sys-
evidence about its effect in hip fractures (34). Evidence tematic review did not identify any CEAs applicable to the
from RCTs showed that romosozumab may have United States for either treatment (34). The evidence from
resulted in no differences in serious adverse events the published CEAs was insufficient to conclude economic
(moderate certainty) or withdrawals due to adverse value of sequential treatments for osteoporosis (34).
events (low certainty) compared with placebo (34). Indirect evidence from a single RCT extension with high
Romosozumab increased risk for cardiovascular events risk of bias was used in CEAs of sequential therapy with
abaloparatide or teriparatide followed by alendronate
compared with alendronate (hazard ratio, 1.9 [CI, 1.1 to
(74–76). Because teriparatide and romosozumab should
3.1]) (21, 34, 60).
be followed by bisphosphonates after discontinuation,
Benefits and Harms of Sequential Therapy
the absolute cost would be higher than the cost of
Evidence from RCTs that looked explicitly at sequen- monotherapy, although the cost-effectiveness of sequential
therapy has not been examined (34). Romosozumab and
tial therapy with bisphosphonates after initial treatment
teriparatide are administered by subcutaneous injection,
with denosumab, romosozumab, or teriparatide was lim-
but teriparatide can be administered by self-injection,
ited (34, 73). Moderate-certainty evidence from a single
whereas romosozumab is often injected by clinicians (Table),
large RCT (60) showed that romosozumab followed by
increasing the overall cost of treatment.
alendronate probably reduced all clinical fractures com-
pared with placebo and probably reduced hip fractures Treatments to Reduce Fractures in Adults With
(ARD, 12 fewer events per 1000 patients), clinical verte- Low Bone Mass
bral fractures (ARD, 13 fewer events per 1000 patients), any Recommendation 4: ACP suggests that clinicians take an
clinical fracture (ARD, 33 fewer events per 1000 patients), individualized approach regarding whether to start pharma-
and radiographic vertebral fractures (ARD, 40 fewer events cologic treatment with a bisphosphonate in females over the
per 1000 patients) compared with a bisphosphonate alone age of 65 with low bone mass (osteopenia) to reduce the
at 12- to 36-month outcome assessment, without higher risk risk of fractures (conditional recommendation; low-certainty
for serious harms or withdrawal due to adverse effects (Table evidence).
1a of Supplement Appendix 1 and Table 2a of Supplement
Rationale
Appendix 2) (34).
Evidence was limited on treatments in adults with low
Applicability
bone mass and was largely informed by a single trial in older
Primary studies of romosozumab or teriparatide en- females that showed zoledronate may reduce any clinical or
rolled postmenopausal females (mean age, >74 years) vertebral fractures (34). Fracture prevention in females with
low bone mass needs to be balanced with harms and costs of
with osteoporosis and very high risk for fracture (Table 1a
bisphosphonates based on an individualized assessment of
of Supplement Appendix 1 and Table 2a of Supplement
baseline risk for fractures. Diagnostic criteria for low bone
Appendix 2) (34). An estimated 10% of females older
mass in females varied in the primary studies (Table 4c of
than 50 years in the general U.S. population would be
Supplement Appendix 4). The effectiveness across different
characterized as being at very high risk (68) as defined by individual bisphosphonates has not been directly evaluated in
the level of risk in females enrolled in RCTs of romosozu- females with low bone mass.
mab (Table 4a of Supplement Appendix 4). Primary stud- The systematic review did not identify any studies report-
ies enrolled postmenopausal females with osteoporosis ing on fracture outcomes for males with low bone mass or
who were already taking vitamin D, calcium, or both on differences in treatment outcomes by sex (34). Because
supplements (Table 4a of Supplement Appendix 4) (34). the certainty of evidence was low in females, further extrapo-
Because this is a conditional recommendation for females, we lation downgraded the certainty in males to insufficient due

to indirectness (34). Therefore, evidence was very uncertain long-term harms (34). Therefore, clinicians should consider
to make a recommendation for or against treatment in males stopping bisphosphonate treatment after 5 years unless the
with low bone mass. patient has a strong indication for treatment continuation.
The decision for a temporary bisphosphonate treat-
Benefits and Harms of Bisphosphonates ment discontinuation (holiday) and its duration should be
Low-certainty evidence from a long-term (6 years) individualized and should be based on baseline risk for
RCT of older females with higher baseline risk for fracture fractures, type of medication and its half-life in bone,
(2.3%) than older females with low bone mass (34, 77) benefits, and harms (higher risk for fracture due to drug
showed that zoledronate may have reduced any clinical discontinuation).
or vertebral fractures, although evidence was very uncer- Females initially treated with an anabolic agent
tain for the effect on hip fractures, withdrawals due to should be offered an antiresorptive agent after discontin-
adverse events, or risk for atrial fibrillation (Table 3a of uation to preserve gains and because of serious risk for
Supplement Appendix 3) (34, 77, 78). Evidence showed rebound and multiple vertebral fractures (21, 69, 70, 82).
there may have been no differences in serious adverse Older adults (for example, those aged >65 years)
events (34). The limited evidence on the effects of alen- with osteoporosis may be at increased risk for falls and other
dronate or risedronate on fractures was very uncertain adverse events due to polypharmacy or drug interactions.
(insufficient) (34). Individualized treatment selection should address contraindi-
cations and cautions for drugs indicated to treat osteoporo-
Applicability sis based on comorbidities and concomitant medications
The RCT enrolled females aged 65 years or older (Tables 1j and 1k of Supplement Appendix 1) as well as
diagnosed with low bone mass at either the total hip or reassessment of other drugs associated with higher risk for
the femoral neck on either side. Females with osteoporo- falls and fractures.
sis at 1 hip site, history of nonvertebral fracture (in 24%), prev- There is variable risk for low bone mass in trans-
alent vertebral fracture (in 13%), and a median 10-year risk gender persons based on age at gonadectomy, therapy
for osteoporotic fracture of 12% were also eligible for the trial with sex hormones, distribution of comorbidities, and
(77) (Table 4c of Supplement Appendix 4). behavioral risk factors for osteoporosis and fractures.
When considering the potential risk for fractures, history
Values and Preferences of gonadectomy (including age) and sex steroid therapy
The systematic review did not identify any studies of should be considered in treatment decisions for second-
patient values and preferences in adults with low bone ary osteoporosis.
mass (34).
Costs EVIDENCE GAPS AND RESEARCH NEEDS

The systematic review did not identify any CEAs ap- Future RCTs should be designed to shed light on long-
plicable to the United States in adults with low bone term comparative benefits and harms from all available treat-
mass, but as previously noted, bisphosphonates are a ments in patients with primary osteoporosis or low bone
less expensive option and provide patients with choices mass, specifically in less-studied populations, such as pre-
for medication route and frequency (34). menopausal females, males, intersex persons, transgender
persons after any transitioning treatment, residents of long-
CLINICAL CONSIDERATIONS term care facilities, and people with multimorbidity and poly-
Clinicians should prescribe generic medications if pos- pharmacy. More studies should assess whether fracture out-
sible rather than more expensive brand-name medications. comes vary depending on baseline risk for fracture and prior
Clinicians treating adults with osteoporosis should response to treatments. Benefits and harms from delayed
encourage adherence to recommended treatments and (83–85) or off-label longer treatment duration with denosu-
healthy lifestyle modifications, including exercise, and mab or anabolic treatments should be examined in well-
counseling for evaluation and prevention of falls. designed, real-world evidence studies.
Adequate calcium and vitamin D intake should be
part of fracture prevention in all adults with low bone Areas With Inconclusive Evidence
mass or osteoporosis. Evidence on benefits and harms was inconclusive to rec-
Clinicians should assess baseline risk for fracture ommend for or against PTHrP (abaloparatide) or SERMs (ralox-
based on individualized assessment of bone density, his- ifene, bazedoxifene) (Table 1a of Supplement Appendix 1 and
tory of fractures, response to prior treatments for osteo- Table 2a of Supplement Appendix 2). Long-term safety of
porosis, and multiple risk factors for fractures (Appendix abaloparatide in humans has yet to be determined. The
Table 3). There are many available risk assessment tools included studies provided sparse data to assess whether
with varying predictive value, which were not evaluated treatment benefits and harms varied according to baseline
in the systematic review (34) or in this guideline. risk for fracture, age (Table 1h of Supplement Appendix 1
Current evidence suggests that increasing the du- and Table 2c of Supplement Appendix 2), race, and ethnic-
ration of bisphosphonate therapy to longer than 3 to 5 years ity. Ongoing studies are expected to provide evidence on
reduces risk for new vertebral fractures but not risk for other the benefits and harms of romosozumab and combined
fractures (34, 79–81). However, there is increased risk for therapies in males with osteoporosis (86–91).

Areas With No Evidence conflicts_cgc.htm. Disclosures can also be viewed at www.
None of the included studies assessed long-term bene- acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=
fits and harms of pharmacologic therapy compared with M22-1034.
nonpharmacologic therapy, abaloparatide, romosozu-
mab, or sequential therapy with available drugs for Corresponding Author: Amir Qaseem, MD, PhD, MHA,
adults with primary osteoporosis. Treatments to mitigate American College of Physicians, 190 N. Independence Mall West,
rebound bone loss in patients with contraindications to Philadelphia, PA 19106; e-mail, aqaseem@acponline.org.
bisphosphonates or harms after bisphosphonate treatment
are unknown. No included studies assessed effects of ana- Correction: This article was amended on 16 May 2023 to correct
bolic drugs on fracture prevention in patients with low bone reporting and editorial errors. The Supplement has also been
mass and multiple risk factors for fractures. No included stud- corrected. None of the corrections affect the overall conclusions.
ies specifically examined fracture prevention in transgender A correction has been published (doi:10.7326/L23-0120).
persons with osteoporosis or low bone mass.
Author contributions are available at Annals.org.
From American College of Physicians, Philadelphia, Pennsylvania
(A.Q., I.E., T.S.); Centers for Disease Control and Prevention, Atlanta,
Georgia (L.A.H.); and Oregon Health & Science University, Portland, References
Oregon (T.G.C.). 1. Wright NC, Looker AC, Saag KG, et al. The recent prevalence of
osteoporosis and low bone mass in the United States based on
Note: Clinical guidelines are meant to guide care based on the bone mineral density at the femoral neck or lumbar spine. J Bone
best available evidence and may not apply to all patients or individ- Miner Res. 2014;29:2520-6. [PMID: 24771492] doi:10.1002/jbmr.2269
ual clinical situations. They should not be used as a replacement for 2. Curry SJ, Krist AH, Owens DK, et al; US Preventive Services Task
a clinician's judgment. Any reference to a product or process con- Force. Screening for osteoporosis to prevent fractures: US Preventive
tained in a guideline is not intended as an endorsement of any spe- Services Task Force recommendation statement. JAMA. 2018;319:
2521-31. [PMID: 29946735] doi:10.1001/jama.2018.7498
cific commercial product. All ACP clinical guidelines are considered
3. Lee SB, Park Y, Kim DW, et al. Association between mortality risk
automatically withdrawn or invalid 5 years after publication or once
and the number, location, and sequence of subsequent fractures in
an update has been issued. the elderly. Osteoporos Int. 2021;32:233-41. [PMID: 32820370]
doi:10.1007/s00198-020-05602-x
Disclaimer: The findings and conclusions in this article are those 4. Rizkallah M, Bachour F, Khoury ME, et al. Comparison of morbid-
of the authors and do not necessarily represent the official posi- ity and mortality of hip and vertebral fragility fractures: which one
tion of the Centers for Disease Control and Prevention. has the highest burden. Osteoporos Sarcopenia. 2020;6:146-50.
[PMID: 33102809] doi:10.1016/j.afos.2020.07.002
Acknowledgment: The Clinical Guidelines Committee would like 5. Crandall CJ, Hunt RP, LaCroix AZ, et al. After the initial fracture in
postmenopausal women, where do subsequent fractures occur.
to acknowledge members of the ACP Guidelines Public Panel for
EClinicalMedicine. 2021;35:100826. [PMID: 34124629] doi:10.1016/j.
their review and comments on the article from a patient perspective:
eclinm.2021.100826
Cynthia Appley, Ray Haeme, Billy Oglesby, James Pantelas, Missy 6. Sarafrazi N, Wambogo EA, Shepherd JA. Osteoporosis or low
Carson Smith, and Lelis Vernon. The authors also thank Jennifer bone mass in older adults: United States, 2017-2018. NCHS Data
Yost, RN, PhD, for her methodological review and input on the draft Brief. 2021:1-8. [PMID: 34029181]
guideline. 7. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and
economic burden of osteoporosis-related fractures in the United States,
Financial Support: Financial support for the development of this 2005-2025. J Bone Miner Res. 2007;22:465-75. [PMID: 17144789]
guideline came exclusively from the ACP operating budget. 8. Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trends in osteoporosis
and low bone mass in older US adults, 2005-2006 through 2013-2014.
Osteoporos Int. 2017;28:1979-88. [PMID: 28315954] doi:10.1007/
Disclosures: All financial and intellectual disclosures of interest were
s00198-017-3996-1
declared, and potential conflicts were discussed and managed. Dr. 9. Roux C, Thomas T, Paccou J, et al. Refracture and mortality following
Mustafa disclosed a high-level conflict (site principal investigator for hospitalization for severe osteoporotic fractures: the Fractos Study. JBMR
industry-funded trial) during work and upon identification was Plus. 2021;5:e10507. [PMID: 34258503] doi:10.1002/jbm4.10507
recused from further discussion, authorship, and voting. Dr. Williams 10. Riska BSL, Fors en L, Omsland TK, et al. Does the association of
acquired a high-level conflict (household member receiving industry comorbidity with 1-year mortality after hip fracture differ according
consulting fees) during work development and upon identification to gender? The Norwegian Epidemiologic Osteoporosis Studies
was recused from further discussion, authorship, and voting. Dr. Wilt (NOREPOS). J Am Geriatr Soc. 2018;66:553-8. [PMID: 29427505]
was recused from authorship and voting due to a moderate-level doi:10.1111/jgs.15207
conflict of interest (household member recently authored relevant 11. Kannegaard PN, van der Mark S, Eiken P, et al. Excess mortality
in men compared with women following a hip fracture. National
publications and served on technical expert panel for supporting sys-
analysis of comedications, comorbidity and survival. Age Ageing.
tematic review). Drs. Crandall and Owens were recused from author-
2010;39:203-9. [PMID: 20075035] doi:10.1093/ageing/afp221
ship and voting due to moderate-level conflicts of interest (recently 12. Herrera A, Lobo-Escolar A, Mateo J, et al. Male osteoporosis: a
authored relevant publications). A record of disclosures of interest review. World J Orthop. 2012;3:223-34. [PMID: 23362466] doi:10.5312/
and management of conflicts is kept for each Clinical Guidelines wjo.v3.i12.223
Committee meeting and conference call and can be viewed at 13. Tran O, Silverman S, Xu X, et al. Long-term direct and indirect
www.acponline.org/clinical_information/guidelines/guidelines/ economic burden associated with osteoporotic fracture in US

postmenopausal women. Osteoporos Int. 2021;32:1195-1205. 29. Simpson EL, Martyn-St James M, Hamilton J, et al. Clinical
[PMID: 33411007] doi:10.1007/s00198-020-05769-3 effectiveness of denosumab, raloxifene, romosozumab, and teri-
14. Hansen D, Pelizzari PM, Pyenson BS. Medicare cost of paratide for the prevention of osteoporotic fragility fractures: a sys-
osteoporotic fractures: 2021 updated report. Milliman; 30 March tematic review and network meta-analysis. Bone. 2020;130:115081.
2021. Accessed at www.milliman.com/en/insight/medicare-cost-of- [PMID: 31626995] doi:10.1016/j.bone.2019.115081
osteoporotic-fractures-2021-updated-report on 2 December 2022. 30. Davis S, Simpson E, Hamilton J, et al. Denosumab, raloxifene,
15. Hansen D, Bazell C, Pelizzari P, et al. Medicare cost of romosozumab and teriparatide to prevent osteoporotic fragility
osteoporotic fractures. Milliman; August 2019. Accessed at https:// fractures: a systematic review and economic evaluation. Health Technol
assets.milliman.com/ektron/Medicare_cost_of_osteoporotic_fractures.pdf Assess. 2020;24:1-314. [PMID: 32588816] doi:10.3310/hta24290
on 2 December 2022. 31. Fink HA, MacDonald R, Forte ML, et al. Long-term drug therapy
16. Qaseem A, Snow V, Shekelle P, et al; Clinical Efficacy Assessment and drug discontinuations and holidays for osteoporosis fracture
Subcommittee of the American College of Physicians. Pharmacologic prevention: a systematic review. Ann Intern Med. 2019;171:37-50.
treatment of low bone density or osteoporosis to prevent fractures: a [PMID: 31009947] doi:10.7326/M19-0533
clinical practice guideline from the American College of Physicians. Ann 32. Kline GA, Morin SN, Feldman S, et al. Diminishing value from multi-
Intern Med. 2008;149:404-15. [PMID: 18794560] ple serial bone densitometry in women receiving antiresorptive medica-
17. Qaseem A, Snow V, Shekelle P, et al; Clinical Efficacy tion for osteoporosis. J Clin Endocrinol Metab. 2021;106:2718-25.
Assessment Subcommittee of the American College of Physicians. [PMID: 33784384] doi:10.1210/clinem/dgab211
Screening for osteoporosis in men: a clinical practice guideline from 33. World Health Organization. Prevention and Management of
the American College of Physicians. Ann Intern Med. 2008;148:680-4. Osteoporosis: Report of a WHO Scientific Group. WHO Technical
[PMID: 18458281] Report Series; 921. 2003. Accessed at https://apps.who.int/iris/
18. Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines bitstream/handle/10665/42841/WHO_TRS_921.pdf?sequence=1 on
Committee of the American College of Physicians. Treatment of December 6 2022.
low bone density or osteoporosis to prevent fractures in men and 34. Ayers C, Kansagara D, Lazur B, et al. Effectiveness and safety of
women: a clinical practice guideline update from the American College treatments to prevent fractures in people with low bone mass or
of Physicians. Ann Intern Med. 2017;166:818-39. [PMID: 28492856] primary osteoporosis: a living systematic review and network meta-
doi:10.7326/M15-1361 analysis for the American College of Physicians. Ann Intern Med.
2023;176:182-195. doi:10.7326/M22-0684
19. Prolia® (denosumab). Highlights of prescribing information.
35. Kehoe T, Blind E, Janssen H. Regulatory aspects of the develop-
Accessed at www.accessdata.fda.gov/drugsatfda_docs/label/2011/
ment of drugs for metabolic bone diseases - FDA and EMA per-
125320s5s6lbl.pdf on 29 November 2022.
spective. Br J Clin Pharmacol. 2019;85:1208-12. [PMID: 30335197]
20. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and man-
doi:10.1111/bcp.13791
agement of discontinuation of denosumab therapy: a systematic
36. Beaudoin C, Moore L, Gagn e M, et al. Performance of predic-
review and position statement by ECTS. J Clin Endocrinol Metab.
tive tools to identify individuals at risk of non-traumatic fracture: a
2020. [PMID: 33103722] doi:10.1210/clinem/dgaa756
systematic review, meta-analysis, and meta-regression. Osteoporos
21. EVENITYTM (romosozumab-aqqg) injection, for subcutaneous use.
Int. 2019;30:721-40. [PMID: 30877348] doi:10.1007/s00198-019-
Highlights of prescribing information. Accessed at www.accessdata.
04919-6
fda.gov/drugsatfda_docs/nda/2019/761062Orig1s000Lbl.pdf on 29
37. El-Hajj Fuleihan G, Chakhtoura M, Cauley JA, et al. Worldwide frac-
November 2022.
ture prediction. J Clin Densitom. 2017;20:397-424. [PMID: 28734709]
22. Vestergaard Kvist A, Faruque J, Vallejo-Yagüe E, et al.
doi:10.1016/j.jocd.2017.06.008
Cardiovascular safety profile of romosozumab: a pharmacovigilance
38. Kanis JA, Harvey NC, Johansson H, et al. Overview of fracture pre-
analysis of the US Food and Drug Administration Adverse Event
diction tools. J Clin Densitom. 2017;20:444-50. [PMID: 28716500]
Reporting System (FAERS). J Clin Med. 2021;10. [PMID: 33924496] doi:10.1016/j.jocd.2017.06.013
doi:10.3390/jcm10081660 39. Marques A, Ferreira RJ, Santos E, et al. The accuracy of osteo-
23. EVISTA (raloxifene hydrochloride) Tablet for Oral Use. Highlights of porotic fracture risk prediction tools: a systematic review and meta-
prescribing information. Accessed at www.accessdata.fda.gov/ analysis. Ann Rheum Dis. 2015;74:1958-67. [PMID: 26248637]
drugsatfda_docs/label/2007/022042lbl.pdf on 29 November 2022. doi:10.1136/annrheumdis-2015-207907
24. Miller PD, Hattersley G, Riis BJ, et al; ACTIVE Study Investigators. 40. Hassett MJ, Somerfield MR, Baker ER, et al. Management of
Effect of abaloparatide vs placebo on new vertebral fractures in male breast cancer: ASCO guideline. J Clin Oncol. 2020;38:1849-
postmenopausal women with osteoporosis: a randomized clinical 63. [PMID: 32058842] doi:10.1200/JCO.19.03120
trial. JAMA. 2016;316:722-33. [PMID: 27533157] doi:10.1001/jama. 41. Joseph JS, Lam V, Patel MI. Preventing osteoporosis in men
2016.11136 taking androgen deprivation therapy for prostate cancer: a system-
25. Greenspan SL, Fitzpatrick LA, Mitlak B, et al. Abaloparatide fol- atic review and meta-analysis. Eur Urol Oncol. 2019;2:551-61.
lowed by alendronate in women ≥80 years with osteoporosis: post [PMID: 31411986] doi:10.1016/j.euo.2018.11.001
hoc analysis of ACTIVExtend. Menopause. 2020;27:1137-42. [PMID: 42. Shapiro CL, Van Poznak C, Lacchetti C, et al. Management of
32665529] doi:10.1097/GME.0000000000001593 osteoporosis in survivors of adult cancers with nonmetastatic dis-
26. Lv F, Cai X, Yang W, et al. Denosumab or romosozumab ther- ease: ASCO clinical practice guideline. J Clin Oncol. 2019;37:2916-
apy and risk of cardiovascular events in patients with primary osteoporo- 46. [PMID: 31532726] doi:10.1200/JCO.19.01696
sis: systematic review and meta-analysis. Bone. 2020;130:115121. 43. Tremollieres FA, Ceausu I, Depypere H, et al. Osteoporosis
[PMID: 31678488] doi:10.1016/j.bone.2019.115121 management in patients with breast cancer: EMAS position state-
27. Kaveh S, Hosseinifard H, Ghadimi N, et al. Efficacy and safety of ment. Maturitas. 2017;95:65-71. [PMID: 27802892] doi:10.1016/j.
romosozumab in treatment for low bone mineral density: a system- maturitas.2016.10.007
atic review and meta-analysis. Clin Rheumatol. 2020;39:3261-76. 44. Qaseem A, Kansagara D, Lin JS, et al; Clinical Guidelines
[PMID: 32385757] doi:10.1007/s10067-020-04948-1 Committee of the American College of Physicians. The develop-
28. Migliorini F, Maffulli N, Colarossi G, et al. Effect of drugs on ment of clinical guidelines and guidance statements by the Clinical
bone mineral density in postmenopausal osteoporosis: a Bayesian Guidelines Committee of the American College of Physicians: update
network meta-analysis. J Orthop Surg Res. 2021;16:533. [PMID: of methods. Ann Intern Med. 2019;170:863-70. [PMID: 31181568]
34452621] doi:10.1186/s13018-021-02678-x doi:10.7326/M18-3290

45. Qaseem A, Wilt TJ, Forciea MA, et al; Clinical Guidelines 60. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendro-
Committee of the American College of Physicians. Disclosure of nate for fracture prevention in women with osteoporosis. N Engl J Med.
interests and management of conflicts of interest in clinical guidelines 2017;377:1417-27. [PMID: 28892457] doi:10.1056/NEJMoa1708322
and guidance statements: methods from the Clinical Guidelines 61. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab
Committee of the American College of Physicians. Ann Intern Med. treatment in postmenopausal women with osteoporosis. N Engl J
2019;171:354-61. [PMID: 31426089] doi:10.7326/M18-3279 Med. 2016;375:1532-43. [PMID: 27641143]
46. Schünemann H, Broz_ ek J, Guyatt G, et al, eds. Handbook for 62. Cosman F, Crittenden DB, Ferrari S, et al. Romosozumab FRAME
grading the quality of evidence and the strength of recommendations study: a post hoc analysis of the role of regional background fracture
using the GRADE approach. Updated October 2013. Accessed at risk on nonvertebral fracture outcome. J Bone Miner Res. 2018;33:
http://gdt.guidelinedevelopment.org/app/handbook/handbook.html 1407-16. [PMID: 29750828] doi:10.1002/jbmr.3439
on 1 July 2022. 63. Nakamura T, Sugimoto T, Nakano T, et al. Randomized Teriparatide
47. Akl EA, Meerpohl JJ, Elliott J, et al; Living Systematic Review [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy
Network. Living systematic reviews: 4. Living guideline recommen- Research (TOWER) trial for examining the reduction in new vertebral
dations. J Clin Epidemiol. 2017;91:47-53. [PMID: 28911999] fractures in subjects with primary osteoporosis and high fracture risk. J
doi:10.1016/j.jclinepi.2017.08.009 Clin Endocrinol Metab. 2012;97:3097-3106. [PMID: 22723322]
48. Willems D, Javaid MK, Pinedo-Villanueva R, et al. Importance doi:10.1210/jc.2011-3479
of time point-specific indirect treatment comparisons of osteoporo- 64. Fujita T, Fukunaga M, Itabashi A, et al. Once-weekly injection of
sis treatments: a systematic literature review and network meta- low-dose teriparatide (28.2 μg) reduced the risk of vertebral fracture
analyses. Clin Ther. 2022;44:81-97. [PMID: 35058055] doi:10.1016/ in patients with primary osteoporosis. Calcif Tissue Int. 2014;94:170-5.
j.clinthera.2021.11.015 [PMID: 23963633] doi:10.1007/s00223-013-9777-8
49. Nevitt MC, Ettinger B, Black DM, et al. The association of 65. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid
radiographically detected vertebral fractures with back pain and hormone (1-34) on fractures and bone mineral density in postmeno-
function: a prospective study. Ann Intern Med. 1998;128:793-800. pausal women with osteoporosis. N Engl J Med. 2001;344:1434-41.
[PMID: 9599190] [PMID: 11346808] doi:10.1056/NEJM200105103441904
50. Boonen S, Orwoll E, Magaziner J, et al; HORIZON Recurrent 66. Al-Saleh Y, Al-Daghri NM, Sabico S, et al. Diagnosis and man-
Fracture Trial. Once-yearly zoledronic acid in older men compared with agement of osteoporosis in postmenopausal women in Gulf
women with recent hip fracture. J Am Geriatr Soc. 2011;59:2084-90.
Cooperation Council (GCC) countries: consensus statement of the
[PMID: 22091563] doi:10.1111/j.1532-5415.2011.03666.x
GCC countries' osteoporosis societies under the auspices of the
51. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zole-
European Society for Clinical and Economic Aspects of Osteoporosis
dronic acid therapy in men with osteoporosis. N Engl J Med. 2012;
and Osteoarthritis (ESCEO). Arch Osteoporos. 2020;15:109. [PMID:
367:1714-23. [PMID: 23113482] doi:10.1056/NEJMoa1204061
32700153] doi:10.1007/s11657-020-00778-5
52. Nakamura T, Fukunaga M, Nakano T, et al. Efficacy and safety of
67. Sanchez-Rodriguez D, Bergmann P, Body JJ, et al. The Belgian
once-yearly zoledronic acid in Japanese patients with primary osteo-
Bone Club 2020 guidelines for the management of osteoporosis in
porosis: two-year results from a randomized placebo-controlled dou-
postmenopausal women. Maturitas. 2020;139:69-89. [PMID: 32747044]
ble-blind study (ZOledroNate treatment in Efficacy to osteoporosis;
doi:10.1016/j.maturitas.2020.05.006
ZONE study). Osteoporos Int. 2017;28:389-98. [PMID: 27631091]
68. Kanis JA, Johansson H, Harvey NC, et al. An assessment of
doi:10.1007/s00198-016-3736-y
intervention thresholds for very high fracture risk applied to the
53. Barrionuevo P, Gionfriddo MR, Castaneda-Guarderas A, et al.
NOGG guidelines: a report for the National Osteoporosis Guideline
Women's values and preferences regarding osteoporosis treatments: a
Group (NOGG). Osteoporos Int. 2021;32:1951-60. [PMID: 33813622]
systematic review. J Clin Endocrinol Metab. 2019;104:1631-6. [PMID:
doi:10.1007/s00198-021-05942-2
30907968] doi:10.1210/jc.2019-00193
54. Morizio P, Burkhart JI, Ozawa S. Denosumab: a unique perspective 69. McClung MR, Brown JP, Diez-Perez A, et al. Effects of 24
on adherence and cost-effectiveness compared with oral bisphospho- months of treatment with romosozumab followed by 12 months of
nates in osteoporosis patients. Ann Pharmacother. 2018;52:1031-41. denosumab or placebo in postmenopausal women with low bone
[PMID: 29616561] doi:10.1177/1060028018768808 mineral density: a randomized, double-blind, phase 2, parallel group
55. Hiligsmann M, Reginster JY, Tosteson ANA, et al. Recommendations study. J Bone Miner Res. 2018;33:1397-1406. [PMID: 29694685]
for the conduct of economic evaluations in osteoporosis: outcomes doi:10.1002/jbmr.3452
of an experts' consensus meeting organized by the European 70. Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teripara-
Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis tide transitions in postmenopausal osteoporosis (the DATA-Switch study):
and Musculoskeletal Diseases (ESCEO) and the US branch of the extension of a randomised controlled trial. Lancet. 2015;386:1147-55.
International Osteoporosis Foundation. Osteoporos Int. 2019;30:45-57. [PMID: 26144908] doi:10.1016/S0140-6736(15)61120-5
[PMID: 30382319] doi:10.1007/s00198-018-4744-x 71. FORTEO (teriparatide injection) for subcutaneous use. Highlights
56. Albert SG, Reddy S. Clinical evaluation of cost efficacy of drugs of prescribing information. Accessed at www.accessdata.fda.gov/
for treatment of osteoporosis: a meta-analysis. Endocr Pract. 2017;23: drugsatfda_docs/label/2020/021318s053lbl.pdf on 29 November
841-56. [PMID: 28448754] doi:10.4158/EP161678.RA 2022.
57. Silverman S, Agodoa I, Kruse M, et al. Denosumab for elderly 72. Hagino H, Sugimoto T, Tanaka S, et al. A randomized, con-
men with osteoporosis: a cost-effectiveness analysis from the US trolled trial of once-weekly teriparatide injection versus alendronate in
payer perspective. J Osteoporos. 2015;2015:627631. [PMID: 26783494] patients at high risk of osteoporotic fracture: primary results of the
doi:10.1155/2015/627631 Japanese Osteoporosis Intervention Trial-05. Osteoporos Int. 2021;32:
58. Li N, Cornelissen D, Silverman S, et al. An updated systematic 2301-11. [PMID: 34002252] doi:10.1007/s00198-021-05996-2
review of cost-effectiveness analyses of drugs for osteoporosis. 73. Miller SA, St Onge EL, Whalen KL. Romosozumab: a novel agent
Pharmacoeconomics. 2021;39:181-209. [PMID: 33026634] doi:10.1007/ in the treatment for postmenopausal osteoporosis. J Pharm Technol.
s40273-020-00965-9 2021;37:45-52. [PMID: 34752536] doi:10.1177/8755122520967632
59. McClung MR, Boonen S, Törring O, et al. Effect of denosumab 74. Hiligsmann M, Williams SA, Fitzpatrick LA, et al. Cost-effectiveness of
treatment on the risk of fractures in subgroups of women with post- sequential treatment with abaloparatide vs. teriparatide for United States
menopausal osteoporosis. J Bone Miner Res. 2012;27:211-8. [PMID: women at increased risk of fracture. Semin Arthritis Rheum. 2019;49:184-
21976367] doi:10.1002/jbmr.536 96. [PMID: 30737062] doi:10.1016/j.semarthrit.2019.01.006

75. Le QA, Hay JW, Becker R, et al. Cost-effectiveness analysis of se- 83. Lyu H, Yoshida K, Zhao SS, et al. Delayed denosumab injections
quential treatment of abaloparatide followed by alendronate versus and fracture risk among patients with osteoporosis: a population-
teriparatide followed by alendronate in postmenopausal women with based cohort study. Ann Intern Med. 2020;173:516-26. [PMID:
osteoporosis in the United States. Ann Pharmacother. 2019;53:134- 32716706] doi:10.7326/M20-0882
43. [PMID: 30160186] doi:10.1177/1060028018798034 84. Lyu H, Zhao SS, Yoshida K, et al. Delayed denosumab injections
76. Mori T, Crandall CJ, Ganz DA. Cost-effectiveness of sequential and bone mineral density response: an electronic health record-
teriparatide/alendronate versus alendronate-alone strategies in based study. J Clin Endocrinol Metab. 2020;105:1435-44. [PMID:
high-risk osteoporotic women in the US: analyzing the impact of 31894244] doi:10.1210/clinem/dgz321
generic/biosimilar teriparatide. JBMR Plus. 2019;3:e10233. [PMID: 85. Mazziotti G, Betella N, Lania AG. Letter to the editor: “Delayed
31768491] doi:10.1002/jbm4.10233 denosumab injections and bone mineral density response: an elec-
77. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledr- tronic health record-based study” [Letter]. J Clin Endocrinol Metab.
onate in older women with osteopenia. N Engl J Med. 2018;379: 2020;105. [PMID: 32556183] doi:10.1210/clinem/dgaa384
2407-16. [PMID: 30575489] doi:10.1056/NEJMoa1808082 86. Lewiecki EM, Blicharski T, Goemaere S, et al. A phase III random-
78. Reid IR, Horne AM, Mihov B, et al. Anti-fracture efficacy of ized placebo-controlled trial to evaluate efficacy and safety of romoso-
zoledronate in subgroups of osteopenic postmenopausal women: zumab in men with osteoporosis. J Clin Endocrinol Metab. 2018;103:
secondary analysis of a randomized controlled trial. J Intern Med. 3183-93. [PMID: 29931216] doi:10.1210/jc.2017-02163
2019;286:221-9. [PMID: 30887607] doi:10.1111/joim.12901 87. Walker MD, Cusano NE, Sliney J Jr, et al. Combination therapy
79. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years with risedronate and teriparatide in male osteoporosis. Endocrine.
of zoledronic acid treatment of osteoporosis: a randomized exten- 2013;44:237-46. [PMID: 23099796] doi:10.1007/s12020-012-9819-4
sion to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 88. Efficacy and Safety of Zoledronic Acid for the Treatment of
2012;27:243-54. [PMID: 22161728] doi:10.1002/jbmr.1494 Osteoporosis in Men [clinical trial]. Accessed at https://clinicaltrials.
80. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. gov/show/NCT00097825 on 29 November 2022.
Effects of continuing or stopping alendronate after 5 years of treat- 89. Novel Combination Therapy for Osteoporosis in Men (Osteo-Men)
ment: the Fracture Intervention Trial Long-term Extension (FLEX): a [clinical trial]. Accessed at https://clinicaltrials.gov/show/NCT03994172
randomized trial. JAMA. 2006;296:2927-38. [PMID: 17190893] on 29 November 2022.
81. Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years 90. A Study to Compare the Safety and Efficacy of Romosozumab
of zoledronic acid treatment in osteoporosis: a randomized second (AMG 785) Versus Placebo in Men With Osteoporosis (BRIDGE)
extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner [clinical trial]. Accessed at https://clinicaltrials.gov/show/NCT02186171 on
Res. 2015;30:934-44. [PMID: 25545380] doi:10.1002/jbmr.2442 29 November 2022.
82. Reid IR, Billington EO. Drug therapy for osteoporosis in older 91. Combination Risedronate - Parathyroid Hormone Trial in Male
adults. Lancet. 2022;399:1080-92. [PMID: 35279261] doi:10.1016/ Osteoporosis (RPM) [clinical trial]. Accessed at https://clinicaltrials.
S0140-6736(21)02646-5 gov/show/NCT01611571 on 29 November 2022.
DOWNLOAD IMPORTANT REFERENCES TO CITATION MANAGERS
At Annals.org, article citations may be directly downloaded to any of the

following formats: RIS (ProCite, Reference Manager), EndNote,
BibTeX, RefWorks, or MEDLARS.

Author Contributions: Conception and design: A. Qaseem, L.A. Collection and assembly of data: I. Etxeandia-Ikobaltzeta, T.
Hicks, I. Etxeandia-Ikobaltzeta, T. Shamliyan. Shamliyan.
Analysis and interpretation of the data: A. Qaseem, L.A. Hicks,
T. Shamliyan, T.G. Cooney, J.T. Cross, A.J. Obley, J.A. Tice. Web References
Drafting of the article: A. Qaseem, L.A. Hicks, I. Etxeandia- 92. Anderson PA, Freedman BA, Brox WT, et al. Osteoporosis:
Ikobaltzeta, T. Shamliyan, J.T. Cross, J.E. Tufte. recent recommendations and positions of the American Society for
Critical revision for important intellectual content: A. Qaseem, Bone and Mineral Research and the International Society for
L.A. Hicks, I. Etxeandia-Ikobaltzeta, T. Shamliyan, T.G. Cooney, Clinical Densitometry. J Bone Joint Surg Am. 2021;103:741-7.
[PMID: 33587517] doi:10.2106/JBJS.20.01248
J.S. Lin, A.J. Obley, J.A. Tice.
93. International Society for Clinical Densitometry. Adult Official
Final approval of the article: A. Qaseem, L.A. Hicks, I. Etxeandia-
Positions. 2019. Accessed at https://iscd.org/wp-content/uploads/
Ikobaltzeta, T. Shamliyan, T.G. Cooney, J.T. Cross, N. Fitterman,
2021/09/2019-Official-Positions-Adult-1.pdf on 2 December 2022.
J.S. Lin, M. Maroto, A.J. Obley, J.A. Tice, J.E. Tufte. 94. Nakamura T, Nakano T, Ito M, et al; MOVER Study Group.
Statistical expertise: A. Qaseem. Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month
Obtaining of funding: A. Qaseem. intravenous ibandronate versus 2.5 mg/day oral risedronate in
Administrative, technical, or logistic support: A. Qaseem, I. patients with primary osteoporosis. Calcif Tissue Int. 2013;93:137-
Etxeandia-Ikobaltzeta, T. Shamliyan. 46. [PMID: 23644930] doi:10.1007/s00223-013-9734-6
Appendix Figure. Grading the certainty of evidence and strength of recommendations in ACP clinical guidelines using the GRADE
(Grading of Recommendations Assessment, Development and Evaluation) approach.
Grading Certainty of Evidence
High Confident that the true effect lies close to that of the estimate of the effect (the intervention “results in” the effect).
Moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there
Moderate
is a sizeable possibility that it is substantially different (the intervention “probably results in” the effect).
Confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the
Low
effect (the intervention “may result in” the effect).
Grading Strength of Recommendations
Balance of Benefits Applicable Patient

Strength Policy Implications
and Harms Population
Strong (ACP Confidence that the benefits clearly Applies to most patients in most Only strong recommendations could
recommends) outweigh risks and burden or vice circumstances. be considered as quality indicators to
versa. guide the development of accountability,
reporting, and payment programs.
Conditional (ACP Suggests) Benefits probably outweigh the risks Applies to many patients but may differ Policymaking will require substantial
and burden, or vice versa, but there depending on circumstances or patients’ debates and involvement of many
is appreciable uncertainty. values and preferences. stakeholders. Policies are also more
likely to vary between regions. Quality
indicators would have to focus on the
fact that adequate deliberation about
the management options has taken place.
ACP = American College of Physicians.
Annals.org Annals of Internal Medicine • Vol. 176 No. 2 • February 2023

Appendix Table 1. Definitions of Low Bone Mass and Osteoporosis
Condition Definition
Low bone mass (osteopenia) A BMD value at the femoral neck, the lumbar spine, or both that is between 1 and 2.5 SDs below the mean BMD value for
a young woman (18, 92, 93)
Osteoporosis A BMD value at the femoral neck, the lumbar spine, or both that is ≥2.5 SDs below the mean BMD value for a young
woman; osteoporosis may be diagnosed in postmenopausal women and in men aged ≥50 y if the T-score for the lum-
bar spine, total hip, or femoral neck is 2.5 or less (in certain circumstances, the 33% radius [also called the 1/3 radius]
may be used) (18, 92, 93)
The reference standard from which the T-score is calculated is the White female population aged 20–29 y in the NHANES
III database
A uniform White (not adjusted for race) female reference was used for men in all ethnic groups
BMD = bone mineral density; NHANES III = Third National Health and Nutrition Examination Survey.
Appendix Table 2. Osteoporotic Fracture Outcomes Reference Guide*

Fracture Outcome Fracture Location Definition Example
Clinical† Any fracture Any fracture (vertebral or nonvertebral) dis- A patient seeks care for symptoms that are
covered because the patient is sympto- suggestive of fracture after a fall from a
matic; verified by radiograph‡ standing height, and the clinician orders
radiographs by which the fracture is subse-
quently confirmed.
Clinical vertebral Spine A vertebral fracture discovered because the After a fall from a standing height, a patient
patient is symptomatic; verified by seeks care due to symptoms highly sug-
radiograph gestive of vertebral fracture, and the clini-
cian orders radiographs confirming
fracture.
Nonvertebral† All nonspine Clinical fractures outside the spine§, exclud- A patient breaks their tibia during a fall from
ing fractures not considered to be related a standing height, and fracture is subse-
to osteoporosis (e.g., in the toes, skull, quently confirmed by radiograph.
face, or fingers)
Hip Hip Clinical fracture at the top of the femur A patient falls and cannot get up due to hip
pain. Hip fracture is subsequently con-
firmed by radiograph.
Radiographic vertebral Spine Any vertebral fracture appearing on a radio- A study performs spinal radiographs on all
graph||, regardless of whether the patient participants entering the study and again
is symptomatic after treatment.
* Most studies limited data to fragility fractures (i.e., fractures resulting from a fall from a standing height or lower) and radiographic vertebral frac-
tures; pathologic and high-trauma fractures were generally excluded. A combined outcome of any clinical fracture was created specifically for the
network meta-analysis (34).
† Not a GRADE (Grading of Recommendations Assessment, Development and Evaluation) outcome, but analyzed as any clinical fracture for network
meta-analysis.
‡ Major osteoporotic fractures (fractures of hip, spine [clinical], wrist, or humerus) were included as any clinical fracture.
§ Several studies limited nonvertebral fractures to predetermined sites. For example, the MOVER (MOnthly intraVenous ibandronatE versus daily
oral Risedronate) study defined nonvertebral fractures as those at 6 major sites: the femur, the forearm, the humerus, the clavicle, the tibia/fibula,
and the pelvis (94).
|| Most studies used semiquantitative and/or quantitative morphometry assessment to determine prevalent and incident vertebral fractures.
Annals of Internal Medicine • Vol. 176 No. 2 • February 2023 Annals.org

Appendix Table 3. Risk Factors for Osteoporotic Fracture*
Increasing age
Female sex
Postmenopause (females)
Hypogonadism or premature ovarian failure
Low body weight
History of hip fracture in parent
Racial background (White persons are at higher risk than Black persons)
Previous clinical or morphometric vertebral fracture
Previous fracture due to minimal trauma (i.e., previous osteoporotic
fracture)
Rheumatoid arthritis
Current smoking
Current alcohol intake (≥3 drinks daily)
Low bone mineral mass
Vitamin D deficiency
Low calcium intake
Hyperkyphosis
Falling and immobilization
Long-term use of certain medications, the most implicated being gluco-
corticoids, anticoagulants, anticonvulsants, aromatase inhibitors, can-
cer chemotherapeutic drugs, and gonadotrophin-releasing hormone
agonists
* From references 36 to 39.
Annals.org Annals of Internal Medicine • Vol. 176 No. 2 • February 2023

Pharmacologic TX of Primary Osteoporosis or Low Bone Mass To Prevent Fxctures in Adults

Uploaded by

Copyright:

Available Formats

Pharmacologic TX of Primary Osteoporosis or Low Bone Mass To Prevent Fxctures in Adults

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pharmacologic TX of Primary Osteoporosis or Low Bone Mass To Prevent Fxctures in Adults

Uploaded by

Copyright:

Available Formats

CLINICAL GUIDELINE

Pharmacologic Treatment of Primary Osteoporosis or Low Bone

P rimary osteoporosis (osteoporosis that is not secondary

224 © 2023 American College of Physicians

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Table. Medications Licensed in the United States for Treatment of Osteoporosis

Estrogen agonist on bones

OUTCOMES OF INTEREST beneﬁts of the various treatments, we looked at fracture rates

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Figure 1. Treatments to reduce fractures in postmenopausal females with primary osteoporosis.

Treatments to Reduce Fractures in Postmenopausal Females

Hip Fractures, ≥36 Months Clinical Vertebral Fracture, ≥36 Months

Hip Fractures, 12–36 Months Clinical Vertebral Fracture, 12–36 Months

Withdrawal Due to Adverse Events, ≥36 Months SEQUENTIAL THERAPY

Continued on following page

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Serious Adverse Events, ≥36 Months

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Figure 2. Treatments to reduce fractures in males with primary osteoporosis.

Treatments to Reduce Fractures in Males With Primary Osteoporosis

Radiographic Vertebral Fractures, ≥36 Months

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Treatments to Reduce Fractures in Postmenopausal Females

ACP = American College of Physicians.

These recommendations are applicable to bisphospho- Beneﬁts and Harms of Bisphosphonates

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Costs EVIDENCE GAPS AND RESEARCH NEEDS

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

DOWNLOAD IMPORTANT REFERENCES TO CITATION MANAGERS

At Annals.org, article citations may be directly downloaded to any of the

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Grading Certainty of Evidence

Balance of Benefits Applicable Patient

ACP = American College of Physicians.

Annals.org Annals of Internal Medicine • Vol. 176 No. 2 • February 2023

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Appendix Table 2. Osteoporotic Fracture Outcomes Reference Guide*

Annals of Internal Medicine • Vol. 176 No. 2 • February 2023 Annals.org

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

Annals.org Annals of Internal Medicine • Vol. 176 No. 2 • February 2023

Downloaded from https://annals.org by Francisco Fidencio Cons Molina on 01/19/2024.

You might also like