Osteoporosis tto

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Literature review current through: Jul 2014. | This topic last updated: Jan 24, 2014.
INTRODUCTION The treatment of osteoporosis consists of lifestyle measures and pharmacologic
therapy [1]. An overview of the approach to therapy of osteoporosis in postmenopausal women will be
presented here. The diagnosis and evaluation of osteoporosis in postmenopausal women, prevention
of osteoporosis, and the management of osteoporosis in men and premenopausal women are
discussed separately. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in
postmenopausal women" and "Prevention of osteoporosis" and "Treatment of osteoporosis in
men" and "Evaluation and treatment of premenopausal osteoporosis".)
LIFESTYLE MEASURES All postmenopausal women with osteoporosis should receive adequate
calcium and vitamin D. Other important lifestyle measures include exercise, smoking cessation,
counseling on fall prevention, and avoidance of heavy alcohol use. In addition, affected patients
should avoid, if possible, drugs that increase bone loss, such as glucocorticoids. (See "Falls:
Prevention in community-dwelling older persons" and "Pathogenesis, clinical features, and evaluation
of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced
osteoporosis" and "Drugs that affect bone metabolism".)
Calcium/vitamin D An optimal diet for treatment (or prevention) of osteoporosis includes an
adequate intake of calories (to avoid malnutrition), calcium, and vitamin D.
Postmenopausal women should take adequate supplemental elemental calcium (generally 500 to
1000 mg/day), in divided doses, at mealtime, such that their total calcium intake (diet plus
supplements) approximates 1200 mg/day [2]. Women who are getting adequate calcium from dietary
intake alone do not need to take calcium supplements. There is considerable controversy around the
effects of calcium supplements on the risk of cardiovascular disease. This is discussed in detail
separately. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Side effects'.)
Women should also ingest a total of 800 international units of vitamin D daily. Higher doses are
required if they have malabsorption or rapid metabolism of vitamin D due to concomitant
anticonvulsant drug therapy.
Data on the efficacy of calcium and vitamin D replacement for osteoporosis are discussed in detail
elsewhere.
Diet When celiac disease is a major contributor to osteopenia, a gluten-free diet may result in
improvement in bone mineral density [3]. (See "Management of celiac disease in adults".)
Data on the impact of protein intake on bone density are conflicting. While some studies suggest that
higher protein intake may be associated with a lower risk of hip fractures [4] and bone loss [5-8],
others suggest that high protein intake may increase bone resorption and calcium excretion [9]. Thus,
given the conflicting data, we do not recommend modifying protein intake as a strategy for preventing
bone loss.
Exercise Women with osteoporosis (or seeking to prevent it) should exercise (prudently) for at
least 30 minutes three times per week. In prospective cohort studies, exercise was associated with a
reduced risk of hip fracture in older women [10,11]. In a meta-analysis of 10 trials, exercise reduced
the occurrence of overall fractures in older adults (4.8 versus 10.9 percent in the control group,
relative risk [RR] 0.49, 95% CI 0.31-0.76) [12]. The reduction in vertebral fractures was not statistically
significant (three trials, 18 versus 30 percent, RR 0.56, 95% CI 0.3-1.04) [12]. This may be related to
the small number of patients included in the vertebral fracture trials.
Exercise also has beneficial effects on bone mineral density (BMD) in premenopausal and
postmenopausal women [13,14]. A meta-analysis of 43 randomized trials (4320 participants) of
exercise and bone mineral density in postmenopausal women showed a significant positive effect of
exercise on BMD at the lumbar spine (mean difference 0.85, 95% CI 0.62-1.07) and trochanter (mean
difference 1.03, 95% CI 0.56-1.49) compared with controls [14]. A variety of exercise types, including
resistance training, jogging, jumping, and walking, was effective. The most effective type of exercise
for BMD of the femoral neck was non-weight bearing high force exercise (eg, progressive resistance
strength training), whereas a combined program (mixture of more than one exercise type) was most
effective for lumbar spine BMD [14]. The meta-analysis was limited by loss to follow-up and the poor
quality of allocation concealment and blinding.
Overall, the beneficial effect of exercise on bone density is small. However, these changes reflect
areal bone mineral density measurements. It is still uncertain how long-term exercise affects other
measures of bone architecture. Therefore, if exercise does reduce the risk of fracture, it may relate to
changes in parameters other than areal bone mass or to increased muscular strength and decreased
risk of falls [10,15]. (See "Falls: Prevention in community-dwelling older persons", section on
'Exercise'.)
Intensity of exercise There is no convincing evidence that high-intensity exercise, such as
running, is of greater benefit than lower intensity exercise, such as walking. Because enjoyment of the
regimen is important (the benefits of exercise are quickly lost after the woman stops exercising [16]),
we recommend that women pick a regular weight-bearing exercise regimen that they enjoy to
facilitate long-term compliance. Excessive exercise in premenopausal women may lead to weight loss
and amenorrhea, thereby causing osteoporosis. (See "Amenorrhea and infertility associated with
exercise".)
Cessation of smoking We strongly recommend smoking cessation to all women concerned with
their skeletal health because smoking cigarettes accelerates bone loss. One study, as an example,
evaluated female twins who were discordant for smoking [17]. Smoking one pack per day throughout
adult life was associated with a 5 to 10 percent reduction in bone density. Smoking may also negate
the beneficial effect of estrogen therapy in postmenopausal women [18,19]. This may be mediated in
part by acceleration of the metabolism of estrogen, thereby lowering serum estrogen concentrations.
Other There is a growing interest in other nonpharmacologic therapies for osteoporosis. In animal
models, mechanical stimulation from vibration produced anabolic effects on cancellous and cortical
bone [20,21]. Although whole body vibration platforms have been proposed as a nonpharmacologic
therapy for postmenopausal osteoporosis, the available data from randomized trials show minimal to
no improvement in bone mineral density with the use of whole body vibration platforms compared with
sham vibration, walking, or no treatment [22-24]. In most trials, data were evaluated per-protocol,
rather than intention-to-treat. None of the trials evaluated fracture outcomes. In addition, the safety of
vibration therapy in elderly patients has not been carefully examined. Thus, there are insufficient data
to recommend this therapy in postmenopausal women.
PHARMACOLOGIC THERAPY
Candidates for therapy The above measures should be adopted universally to reduce bone loss
in postmenopausal women. Patients with the highest risk of fracture are the ones most likely to benefit
from drug therapy. Fracture risk is determined by a combination of bone mineral density and clinical
risk factors. Particular attention should be paid to treating women with a recent fracture, including hip
fracture, because they are at high risk for a second fracture. (See "Medical consultation for patients
with hip fracture".)
We largely agree with the National Osteoporosis Foundation (NOF) recommendations as outlined
below [25]. We recommend pharmacologic therapy for postmenopausal women with a history of hip
or vertebral fracture or with osteoporosis based upon bone mineral density (BMD) measurement (T-
score -2.5). For the treatment of high risk postmenopausal women with T-scores between -1.0 and -
2.5, we also suggest pharmacologic therapy. We calculate fracture risk using the World Health
Organization (WHO) Fracture Risk Assessment Tool (FRAX website). Although the US-adapted WHO
fracture prediction algorithm and NOF recommendations provide general clinical guidance,
osteoporosis treatment should remain individualized through shared decision-making between patient
and clinician.
Fracture risk assessment In 2008, a WHO task force introduced a Fracture Risk Assessment
Tool (FRAX), which estimates the 10-year probability of hip fracture or major osteoporotic fractures
combined (hip, spine, shoulder, or wrist) for an untreated patient using femoral neck BMD and easily
obtainable clinical risk factors for fracture (table 1). The technical aspects of FRAX are reviewed in
detail separately. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment
tool'.)
The National Osteoporosis Foundation (NOF) released revised osteoporosis treatment and
prevention guidelines based upon FRAX in conjunction with an updated US-specific economic
analysis (table 2) [25]. The revised guidelines are similar to previous treatment recommendations.
The NOF recommends treatment of postmenopausal women (and men 50 years) with a history of
hip or vertebral fracture or with osteoporosis based upon BMD measurement (T-score -2.5). These
recommendations are widely accepted, and clinical trial data support the use of bisphosphonates to
prevent fracture in such individuals. (See "The use of bisphosphonates in postmenopausal women
with osteoporosis" and "Treatment of osteoporosis in men", section on 'Bisphosphonates'.)
The guidelines also provide specific treatment recommendations for postmenopausal women with
osteopenia on BMD (T-score between -1.0 and -2.5). In these individuals, the model suggests that
treatment is cost-effective when the 10-year probability of hip fracture reaches 3 percent or the 10-
year probability of major osteoporotic fractures combined is 20 percent (table 2). These criteria were
chosen on the basis of a US-specific economic analysis, and they have not been assessed in clinical
trials.
The 10-year probability of hip and major osteoporotic fracture can be calculated for individual patients
using the FRAX website (click on Calculation Tool and select country). The FRAX algorithm uses
femoral neck BMD (g/cm
2
) for calculation of fracture probability. BMD from non-hip sites has not been
validated and is, therefore, not recommended for use.
Intervention thresholds have been estimated for other countries based upon assessment of absolute
fracture risk and country-specific analyses. The 2010 Osteoporosis Canada guidelines recommend
pharmacologic therapy to patients at high absolute risk (>20 percent probability for major osteoporotic
fracture over 10 years) and to individuals over age 50 who have a fragility fracture [26]. For those at
moderate risk (10 to 20 percent), the decision to treat should be based upon the presence of
additional risk factors not considered in the risk assessment system and upon individual preference.
In the UK, pharmacologic treatment was cost effective at all ages when the 10-year probability of
major osteoporotic fracture exceeded 7 percent [27]. The UK National Osteoporosis Guideline Group
recommends an age-dependent intervention threshold, which ranges from 7.5 to 30 percent for ages
50 to 80 years [28]. For clinicians in the UK, intervention thresholds may be accessed directly from
the FRAX website (click on Calculation Tool, select UK, and then click on View NOGG Guidance after
entering patient specific information).
Limitations We largely agree with the NOF recommendations. However, the benefit of treatment
based upon absolute fracture risk, rather than BMD criteria alone, has not been assessed in clinical
trials.
The emphasis on absolute fracture risk will increase the proportion of elderly women who are
candidates for therapy. As an example, in a study using data from the Study of Osteoporotic Fracture
(SOF), a prospective cohort of community-dwelling Caucasian women 65 years of age, application of
the revised NOF treatment guidelines resulted in recommendations for pharmacologic therapy for 72
percent of women over 65 years of age and 93 percent of women over 75 [29]. Applying bone density
criteria alone (BMD lower than -2.5 at lumbar spine or femoral neck) resulted in a treatment
recommendation for 50 percent of women in both age groups.
Thus, many more elderly women will be candidates for pharmacologic therapy using the new
guidelines. Whether the selection of patients based upon clinical risk factors and BMD, rather than on
BMD alone, improves benefit in elderly patients has not yet been established.
In addition, the NOF economic analysis estimated drug costs based upon use of generic
bisphosphonates. The use of more expensive drugs increases the 10-year fracture probability at
which intervention is cost effective. NOF guidelines should not be applied to individuals living in
different countries as the NOF guidelines are based upon a US-specific economic analysis.
Intervention thresholds have been estimated for other countries, and country-specific guidelines are
available or are in development. (See 'Fracture risk assessment' above and "Osteoporotic fracture
risk assessment", section on 'Clinical application of fracture risk assessment'.)
Choice of drug In the absence of high quality head-to-head drug comparison trials to determine
the relative efficacy of the individual drugs, choice of therapy should be based upon efficacy, safety,
cost, convenience, and other patient-related factors [30]. For most postmenopausal women with
osteoporosis, we suggest oral bisphosphonates as first-line therapy. We prefer oral bisphosphonates
as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data.
In the absence of randomized trial data that ibandronate reduces hip fracture risk, we
suggest alendronate or risedronate as our choice of bisphosphonate. Because oral alendronate is
available as a generic and is very inexpensive, many insurers in the United States require prior
approval for initial therapy with any bisphosphonate other than oral alendronate.
IV zoledronic acid, which has been demonstrated to reduce vertebral and hip fractures, is available in
many countries for the treatment of postmenopausal osteoporosis. It is a good alternative for
individuals with gastrointestinal intolerance to oral bisphosphonates. IV ibandronate is also available;
however, there is as yet no direct fracture prevention data for IV ibandronate. (See "The use of
bisphosphonates in postmenopausal women with osteoporosis".)
There is no consensus on the optimal use of denosumab. Although we prefer oral bisphosphonates
as initial therapy, denosumab could be used as initial therapy in certain patients at high risk for
fracture, such as older patients who have difficulty with the dosing requirements of oral
bisphosphonates. In addition, denosumab may have a role in patients who are intolerant of or
unresponsive to other therapies and in those with impaired renal function. (See "Denosumab for
osteoporosis".)
Strontium ranelate (available outside of North America) may be appropriate for some women who
cannot tolerate or are unable to take oral or intravenous bisphosphonates. (See 'Strontium
ranelate' below.)
Since the antiresorptive effects of raloxifene are less than those of bisphosphonates, we reserve the
use of this drug for patients who cannot tolerate any bisphosphonates or for women with osteoporosis
and increased risk of invasive breast cancer. (See "Selective estrogen receptor modulators for
prevention and treatment of osteoporosis"and "Selective estrogen receptor modulators and
aromatase inhibitors for breast cancer prevention", section on 'Raloxifene'.)
Parathyroid hormone (PTH) is an anabolic agent. In contrast to antiresorptive agents, PTH stimulates
bone formation and activates bone remodeling. PTH 1-34 (teriparatide) reduces the risk of vertebral
and non-vertebral fractures. Given its cost, subcutaneous route of administration, long-term safety
concerns, and availability of other agents, PTH is generally not used as a first-line drug for treatment
or prevention of osteoporosis. It is typically used in postmenopausal women (or men) with severe
osteoporosis and fracture or in patients for whom other osteoporosis therapies fail. (See "Parathyroid
hormone therapy for osteoporosis".)
Efficacy A systematic review of 567 trials published between 2005 and 2011 confirmed the
fracture prevention efficacy of multiple agents compared with placebo [31]. Bisphosphonates
(alendronate, risedronate, zoledronic acid, ibandronate), denosumab, raloxifene, and teriparatide
reduce the risk of vertebral fractures. Alendronate, risedronate, zoledronic acid, and denosumab
reduce the risk of hip and other non-vertebral fractures. Strontium ranelate (available outside of North
America) has been shown to reduce vertebral fracture and, to a lesser extent, non-vertebral fracture.
These drugs are reviewed briefly below and in more detail elsewhere.
Bisphosphonates Alendronate, risedronate, and ibandronate are effective for both the prevention
and treatment of osteoporosis. Zoledronic acid (ZA), administered intravenously (IV) once yearly, is
also effective for the treatment of osteoporosis. These drugs increase bone mass and reduce the
incidence of fractures. General principles of bisphosphonate administration, adverse effects, duration
of use, and drug holidays are discussed in detail elsewhere. (See "The use of bisphosphonates in
postmenopausal women with osteoporosis".)
Selective estrogen receptor modulators There are nonskeletal considerations with selective
estrogen receptor modulators that may play an important role in the selection of postmenopausal
women for therapy, including potential beneficial effects on breast cancer risk reduction, but an
increase in thromboembolic events and possibly hot flashes, and no apparent effect on heart disease
or the endometrium. Raloxifene inhibits bone resorption and reduces the risk of vertebral fracture, and
is our SERM of choice because it has eight-year safety and efficacy data and also reduces the risk of
breast cancer. Raloxifene is usually chosen for osteoporosis when there is an independent need for
breast cancer prophylaxis.
Tamoxifen is another selective estrogen receptor modulator used primarily for the prevention and
management of breast cancer. It is not typically used for osteoporosis, but postmenopausal women
who are receiving treatment with tamoxifen for breast cancer are probably receiving effective bone
protection.
Bazedoxifene, another selective estrogen receptor modulator, is available in Europe and Japan for
the treatment of postmenopausal osteoporosis in women at increased risk for fracture. Although it has
similar efficacy as raloxifene in preventing and treating postmenopausal osteoporosis, there are few
long-term safety data, and it has not been adequately studied for breast cancer prevention. It is not
available as a stand-alone drug in the United States; however, it is available in combination with
conjugated estrogen for prevention of osteoporosis [32]. The selective estrogen receptor modulators
are discussed in more detail elsewhere. (See "Selective estrogen receptor modulators for prevention
and treatment of osteoporosis" and "Selective estrogen receptor modulators and aromatase inhibitors
for breast cancer prevention".)
Parathyroid hormone Parathyroid hormone (PTH) seems an unlikely candidate for the treatment
of osteoporosis because of its well-described deleterious effect on bone [33]. However, intermittent
administration of recombinant human PTH (both full-length 1-84 or amino-terminal fragment 1-34)
stimulates bone formation more than resorption and is effective for fracture reduction in women with
osteoporosis. This topic is reviewed in detail elsewhere. (See "Parathyroid hormone therapy for
osteoporosis".)
Denosumab RANKL (receptor activator of nuclear factor kappa-B ligand) is essential for the
function of bone-resorbing osteoclasts; RANKL accelerates osteoclastogenesis when it binds to its
receptor, RANK, but is blocked by osteoprotegerin, which is produced by osteoblasts. Denosumab is
a humanized monoclonal antibody against RANKL that reduces osteoclastogenesis. In several trials,
it has been shown to improve bone mineral density (BMD) and reduce the incidence of new vertebral,
hip, and non-vertebral fractures in postmenopausal women. This topic is reviewed in detail elsewhere.
(See "Denosumab for osteoporosis".)
Strontium ranelate Strontium ranelate, an orally active drug consisting of two atoms of stable
strontium and an organic moiety (ranelic acid), is available for use in Europe for the treatment of
osteoporosis. In animal studies, strontium appears to inhibit bone resorption and increase or have a
neutral effect on bone formation [34-37]. Its mechanism of action in humans is less certain. Based
upon changes in markers of bone formation and resorption in postmenopausal women with
osteoporosis, it appears to have a modest antiresorptive effect, with little effect on bone formation
[38].
A meta-analysis of four trials concluded that there is reasonable evidence that strontium ranelate is
effective for reducing the risk of vertebral fractures and, to a lesser extent, non-vertebral fractures
[39]. Significantly more patients in the strontium than control group had diarrhea (6.5 versus 4.7
percent), venous thromboembolism (2.2 versus 1.5 percent), and pulmonary embolism (0.8 versus
0.4 percent).
It should be noted that a substantial proportion of the increase in BMD during strontium therapy is due
to the physical effect of strontium accumulation in bone tissue [40]. The magnitude of change in BMD
after strontium therapy, therefore, is not indicative of greater fracture risk reduction.
Two of the larger trials in the meta-analysis are described below:
In a three-year trial, 1649 postmenopausal women with osteoporosis and at least one vertebral
fracture were randomly assigned to receive strontium ranelate (2g/day) or placebo [41]. The risk
of new vertebral fractures was decreased significantly by 41 percent during the three-year study
period (21 versus 33 percent; relative risk [RR] = 0.59, 95% CI 0.48-0.73; number needed to
treat to prevent one fracture = nine).
In a larger trial of 5091 postmenopausal women with osteoporosis randomly assigned to
receive strontium (2 g/day) or placebo for five years, the risk of non-vertebral fracture was
decreased in the strontium group compared with placebo (incidence 19 versus 21 percent, RR
0.85, 95% CI 0.73-0.99) [42,43]. In a post hoc analysis of a high risk group (age 74 years and
T-score <-2.4 at baseline), the relative risk of hip fracture was decreased by 43 percent
(incidence 7 versus 10 percent, RR 0.57, 96% CI 0.33-0.97). When the investigators pooled
these results with their previously published trial [41], they calculated that the effect of strontium
was independent of baseline BMD, age, smoking, or number of vertebral fractures [44].
There are few studies evaluating the long-term efficacy and safety of strontium. In an open-label
extension study of two of the trials described above [41,42], 237 postmenopausal women received
strontium for an additional five years [45]. The cumulative incidence of new fractures in years 6 to 10
was similar to that in years 0 to 5 (20.6 versus 18.5 percent, respectively). Over the 10-year period of
continuous strontium treatment, lumbar spine BMD increased annually, whereas BMD of the femoral
neck and total hip increased significantly until year 7 and then remained stable thereafter. In patients
who had received strontium for 10 years, the annual incidence of venous thromboembolism was 0.4
percent. There were no cases of drug-related hypersensitivity skin reactions. Thus, for this small
subset of patients, 10 years of strontium therapy was effective and safe.
During post-marketing surveillance, severe skin reactions (DRESS, Drug Reaction with Eosinophilia
and Systemic Symptoms, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) have been
reported [46]. In a study from France, 199 strontium-associated severe side effects were identified, of
which approximately 25 percent were severe skin reactions and 50 percent were venous
thromboembolic events [47]. In an analysis of patients prescribed strontium by general practitioners in
England, the crude incidence rate of venous thromboembolism within the first 12 months was 6.24
cases per 100 patient-years exposed, higher than the background incidence rate in the UK population
but similar to the rate in elderly populations receiving treatment for postmenopausal osteoporosis [48].
The risk of thromboembolic disease appears to be higher in patients with a history of venous
thromboembolism or who are immobilized (temporarily or permanently). In a 2012 statement, the
European Medicines Agency recommended that clinicians not prescribe strontium to patients with
current venous thromboembolism (VTE), history of VTE, or to patients who are immobilized [49]. In
addition, it should be discontinued if a skin reaction develops, and treatment should not be restarted.
Estrogen/progestin therapy Estrogen-progestin therapy is no longer a first-line approach for the
treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer,
stroke, venous thromboembolism, and perhaps coronary disease (although the risk-benefit profile in
the unopposed estrogen trial was different) [50]. (See "Postmenopausal hormone therapy: Benefits
and risks".)
Possible indications for estrogen-progestin in postmenopausal women include persistent menopausal
symptoms and women with an indication for antiresorptive therapy who cannot tolerate the other
drugs. In the Women's Health Initiative, both combined estrogen-progestin and unopposed estrogen
treatment reduced hip and vertebral fracture risk (figure 1). The use of estrogen for osteoporosis is
reviewed in detail elsewhere. (See "Postmenopausal hormone therapy in the prevention and
treatment of osteoporosis".)
Calcitonin A less popular choice for treatment of osteoporosis is nasal calcitonin. We prefer other
drugs to calcitonin because of its relatively modest effect on BMD and weak antifracture efficacy
compared with bisphosphonates and parathyroid hormone [51]. There is concern is about the long-
term use of calcitonin for osteoporosis and an increase in cancer rates. This is reviewed separately.
(See "Calcitonin in the prevention and treatment of osteoporosis", section on 'Concerns about the use
of calcitonin'.)
Combination therapy We suggest not using combination therapy, as the additional BMD benefits
are small and there is no proven additional fracture benefit.
Although both bisphosphonates and estrogen inhibit bone resorption, they may act through different
mechanisms. Several studies suggest that conjugated estrogens
(0.625 mg/day) and alendronate (10 mg/day) are equally effective in improving bone mineral density
and that the combination is slightly more effective than either alone. (See "Postmenopausal hormone
therapy in the prevention and treatment of osteoporosis".)
Estrogen plus calcitonin [52], estrogen and androgen [53], estrogen plus etidronate [54],
and alendronate and raloxifene [55] also appear to act synergistically on bone density. However,
fracture data are unavailable for these combinations. In addition, the indications for using estrogen
have been limited since the results of the Women's Health Initiative were published.
(See "Postmenopausal hormone therapy: Benefits and risks" and "The use of bisphosphonates in
postmenopausal women with osteoporosis", section on 'Combination therapy'.)
Several trials have reported that PTH plus alendronate (either started concurrently or prior to PTH)
resulted in no additional benefit for spine or hip BMD compared with PTH alone, and the addition of
alendronate may even attenuate the increase in BMD with PTH. Thus, we do not recommend
concurrent PTH-bisphosphonate therapy. Combination therapy and bisphosphonate therapy after
completing a course of PTH are discussed separately. (See "Parathyroid hormone therapy for
osteoporosis", section on 'PTH plus bisphosphonates' and "Parathyroid hormone therapy for
osteoporosis", section on 'After PTH'.)
Some trials have reported that raloxifene (either taken concurrently or prior to PTH) does not
suppress the BMD response to PTH as much as alendronate. Patients previously treated with
raloxifene have a good BMD response to PTH, but the optimal management (continue versus
discontinue raloxifene) is unclear. (See "Parathyroid hormone therapy for osteoporosis", section on
'Combination therapy'.)
Other therapies Additional therapies for postmenopausal osteoporosis are either under
investigation or are used in some countries. We do not routinely use any of these therapies.
Calcitriol The results of clinical trials of calcitriol in postmenopausal osteoporosis have been mixed.
(See "Calcium and vitamin D supplementation in osteoporosis".)
However, calcitriol has been reported to be effective in preventing glucocorticoid-induced and
posttransplant-related bone loss. (See "Prevention and treatment of glucocorticoid-induced
osteoporosis", section on 'Active vitamin D metabolites' and "Osteoporosis after solid organ or stem
cell transplantation", section on 'Calcitriol'.)
Patients treated with calcitriol should be given a low-calcium diet and monitored for hypercalcemia,
hypercalciuria, and renal insufficiency. These potential problems plus the lack of proven consistent
benefit have appropriately limited the use of calcitriol.
Vitamin K Exogenous vitamin K is required for the carboxylation of osteocalcin, which in turn allows
osteocalcin to bind to hydroxyapatite mineral. A vitamin K2 preparation (menatetrenone) is widely
used for the treatment of osteoporosis in Japan.
Observational data suggest that low vitamin K consumption or impaired vitamin K status may be
associated with an increased risk of fracture in older men and women [56,57]. (See "Vitamin K and
the synthesis and function of gamma carboxyglutamic acid".)
Clinical trial data suggest that vitamin K supplementation may reduce bone loss and fracture risk [58].
This was best illustrated in a meta-analysis of 13 trials of oral vitamin K (phytonadione and
menaquinone) supplementation for bone loss and fracture prevention [59]. Both supplements
increased bone mineral density. Seven trials reported fracture data; all were in Japanese patients
(primarily postmenopausal women with osteoporosis) and used menaquinone. Significant reductions
were seen for vertebral, hip, and all non-vertebral fractures (odds ratio 0.40, 0.23, and 0.19,
respectively, with 95% CI of 0.25-0.65, 0.12-0.47, and 0.11-0.35, respectively).
This report should be interpreted with some caution as fracture data are available only in Japanese
women, who may have significant dietary differences from other populations. In addition, the
magnitude of the fracture risk reductions seems unlikely, as it was far greater than what is seen for
other proven therapies, such as bisphosphonates. Furthermore, in subsequent randomized trials in
healthy, older, predominantly Caucasian men and women receiving calcium and vitamin D
supplements, vitamin K (200, 500, or 1000 micrograms phylloquinone daily or 45 mg menatetrenone
daily) did not have any effect on BMD [60-62]. Based upon the available data, we, therefore, do not
recommend routine vitamin K supplementation for the maintenance of skeletal health or the
prevention of fractures in high-risk individuals.
Tibolone Tibolone, a synthetic steroid whose metabolites have estrogenic, androgenic, and
progestagenic properties [63], is used for osteoporosis management in some countries (but is not
available in the US). Tibolone improves bone mineral density in older postmenopausal women with
established osteoporosis and prevents bone loss in early postmenopausal women without
osteoporosis [64-67].
Tibolone also reduces vertebral fracture risk. The Long-Term Intervention on Fractures with Tibolone
(LIFT) trial, a trial designed to examine the effect of tibolone on vertebral fracture in postmenopausal
women, reported a reduction in the absolute risk of vertebral and non-vertebral fracture (8.6 and 6.9
per 1000 person-years, respectively, relative hazards of 0.55, 95% CI 0.41-0.74 and 0.74, 95% CI
0.58-0.93, respectively) [68]. However, this trial was discontinued early due to an excess risk of
stroke.
Other effects of tibolone are discussed separately. (See "Preparations for postmenopausal hormone
therapy", section on 'Tibolone' and "Menopausal hot flashes".)
Folate/vitamin B12 Combination folate and vitamin B12 therapy may lower fracture risk in elderly
patients with residual hemiplegia after an ischemic stroke [69]. This approach has been studied in 625
elderly Japanese women and men randomly assigned to daily folate (5 mg) and vitamin B12 (1500
mcg orally) or placebo. Baseline levels of homocysteine were modestly elevated (approximately
2.7 mg/L [20 micromol/L]) in both groups (reference range 1 to 1.9 mg/L [7.7 to
14.3 micromol/L]), while B12 and folate levels were slightly low.
Supplementation reduced the number of hip fractures compared with placebo (10 versus 43 per 1000
patient-years, respectively). The adjusted relative risk, absolute risk reduction, and number needed to
treat for hip fractures for treatment versus placebo were 0.20 (95% CI 0.08-0.5), 7.1 percent (95% CI
3.6-10.8), and 14 (95% CI 9-28), respectively.
Whether the risk reduction is due to the lowering of serum homocysteine or an increase in B12 is not
known. In addition, it is not known whether this therapeutic approach will be effective in patients with
normal baseline homocysteine, serum B12, and folate concentrations or in other populations.
A predefined secondary analysis of the Heart Outcomes Prevention Evaluation (HOPE)-2 trial
suggests that this approach is not effective in individuals selected on the basis of cardiovascular
disease (rather than fracture risk) [70]. In this trial, adults at high risk for cardiovascular disease were
randomly assigned to treatment with dailyfolic acid (2.5 mg), vitamin B12 (1 mg), and vitamin B6 (50
mg) or placebo. Mean baseline homocysteine concentration was normal
(1.55 mg/L [11.5 micromol/L] in both groups). Vitamin supplementation did not reduce the incidence of
vertebral or non-vertebral fractures compared with placebo. The HOPE-2 trial is reviewed in detail
elsewhere. (See "Overview of homocysteine", section on 'Cardiovascular disease'.)
Although the evidence is limited, we do not recommend supplemental folic acid or vitamin B12 for the
treatment of osteoporosis or primary prevention of fracture.
Androgens Because men have higher bone density than women, it has been suggested that
treatment with androgens might benefit women with osteoporosis. However, the effect of treatment
with androgen plus estrogen on bone mineral density does not appear superior to the effect of
estrogen alone, and androgen has unwelcome virilizing effects [71].
Furthermore, the presumed beneficial effects of testosterone on bone in men may be mediated by its
conversion to estrogen, as evidenced by the marked improvement in low bone mass following
estrogen therapy in men with aromatase deficiency, which impairs the conversion of androgen to
estrogen [72,73].
We do not recommend androgen therapy for osteoporosis management in women. Although
testosterone replacement may improve bone density in women with hypopituitarism, data are limited,
and there are no approved testosterone preparations available for use. (See "Epidemiology and
etiology of osteoporosis in men", section on 'Estrogen' and "Androgen production and therapy in
women", section on 'Other possible benefits'.)
Isoflavones Isoflavones (a type of phytoestrogen) are micronutrient substances that have properties
similar to estrogen. Two types of isoflavones, genistein and daidzein, are found in soybeans,
chickpeas, and lentils and are thought to be the most potent phytoestrogens. (See "Preparations for
postmenopausal hormone therapy", section on 'Phytoestrogens'.) Ipriflavone is a synthetic isoflavone
derivative and is widely available as an over-the-counter product in many countries.
Some studies have reported that phytoestrogens have a beneficial effect on markers of bone
resorption, bone mineral density (BMD), and fracture risk in animal models [74] and in
postmenopausal women [75,76], while others have not [77-79]. The differences may be due, in part,
to the composition of the isoflavones studied. As examples:
In a two year randomized trial of 389 postmenopausal women with T-scores of -1.0 or lower,
genistein (54 mg daily) improved femoral neck and lumbar spine (LS) BMD compared with
placebo (between group differences of 0.06 and 0.10 g/cm
2
, respectively, 95% CIs 0.05-0.07
and 0.08-0.12 g/cm
2
) [80].
In a trial of 474 postmenopausal women with low bone density who were randomly assigned to
receive ipriflavone (200 mg three times daily) or placebo (plus calcium 500 mg/day in both
groups) for three years, there were no differences in bone mineral density or vertebral fracture
rates between the two groups [81]. Lymphocytopenia occurred in 13 percent of the women
taking ipriflavone, the clinical importance of which is not known.
There are no randomized trials that assess the effect of isoflavones on fracture as a primary outcome.
Based upon available data, we do not recommend isoflavone supplements as a strategy to prevent or
treat osteoporosis.
Other effects of isoflavones are reviewed elsewhere. (See "Preparations for postmenopausal
hormone therapy", section on 'Phytoestrogens'.)
Fluoride There is historical interest in fluoride as an anabolic agent for the treatment of
postmenopausal osteoporosis. Although fluoride increases BMD substantially, clinical trials of fluoride
have not consistently demonstrated fracture reduction [82-86]. While some studies demonstrated a
decrease in the incidence of new vertebral fracture [83,84,86], others reported no change [85] or even
an increase in non-vertebral fractures [82,87]. Fluoride impairs bone mineralization, even when the
dose is as low as 20 mg daily [87]. Given the availability of other therapies, including parathyroid
hormone (anabolic agent), we do not recommend fluoride for the treatment of patients with
osteoporosis. (See "Parathyroid hormone therapy for osteoporosis".)
Emerging therapies There are several novel therapies under investigation for the treatment of
osteoporosis. They are in various stages of development. As examples:
Sclerostin inhibitors Sclerostin is produced by osteocytes and inhibits bone formation.
Sclerostin knock-out mice have increased bone formation and high bone mass [88]. It follows,
therefore, that inhibition of sclerostin should enhance osteoblast function and improve bone
mass. In animal models and in a phase I trial in healthy adults, administration of a sclerostin
monoclonal antibody does increase bone mass [89-91].
Similarly, in a phase 2 trial in postmenopausal women, all doses of a monoclonal anti-sclerostin
antibody (romosozumab) increased bone density at the lumbar spine, total hip, and femoral neck
[92]. In this one-year trial, 419 postmenopausal women with low bone mass (T-score between -
2.0 and -3.5 at the lumbar spine, total hip, or femoral neck) were randomly assigned to
subcutaneous romosozumab (variable dosing once monthly or once every three months), an
active comparator (oral alendronate, 70 mg weekly, or subcutaneous teriparatide, 20 mcg daily),
or placebo injections (monthly or every three months). The greatest increase in bone density
was seen in the group receiving romosozumab 210 mg monthly (11.3 percent compared with 4.1
and 7.1 percent in the alendronate and teriparatide groups, respectively). When dosed every
three months (140 or 210 mg), the increase in lumbar spine bone density with romosozumab
was similar to that seen with alendronate (5.5 and 4.1 percent, respectively) and significantly
lower than that achieved with teriparatide (5.5 and 7.1 percent, respectively). There was a
transient increase in bone formation markers and a more sustained decrease in bone resorption
markers, a pattern that has not been seen among available osteoporosis therapies. There was
an increased frequency of injection site reactions in the romosozumab group. Ongoing trials
should provide more information about antifracture efficacy and safety.
Integrin antagonists Integrins mediate the adhesion of osteoclasts to the bone surface, an
important initial step for bone resorption [93].
Cathepsin K inhibitors Cathepsin K is a protease expressed in osteoclasts that plays a role in
osteoclast-mediated bone resorption [94,95]. Cathepsin K degrades organic bone matrix,
primarily type 1 collagen. Cathepsin K inhibitors (eg, Odanacatib) inhibit matrix dissolution,
decrease bone resorption, and improve bone mineral density in postmenopausal women [96-
100].
MONITORING THE RESPONSE TO THERAPY Monitoring the response to therapy is important
for identifying patients who may require a change in therapy (up to one-sixth of women
taking alendronate continue to lose bone) [101]. While there are a number of approaches to
monitoring therapy, there is no consensus on the optimal approach [102-104].
Our approach Our approach is similar to the International Society for Clinical Densitometry
guidelines (see 'Guidelines' below). For patients starting on therapy, we suggest a follow-up dual-
energy X-ray absorptiometry (DXA) of hip and spine after two years, and if bone mineral density
(BMD) is stable or improved, less frequent monitoring thereafter. (See 'Bone mineral density' below.)
Monitoring with markers of bone turnover is an additional option for patients who have conditions that
might interfere with drug absorption or efficacy, such as small bowel resections or other types of
malabsorption, or for patients who are reluctant to take anti-osteoporosis medications regularly. In
such patients, we typically measure fasting urinary N-telopeptide (NTX) or serum carboxy-terminal
collagen crosslinks (CTX) before and three to six months after starting bisphosphonate or other
antiresorptive therapy. A decrease of greater than 50 or 30 percent in urinary NTX excretion or serum
CTX, respectively, provides evidence of compliance and drug efficacy. The patient can be reassured
that the next BMD measurement will likely be stable or improved. In contrast, a decrease in markers
of less than 30 percent may not necessarily indicate treatment failure. However, when this occurs, we
question the patient about possible noncompliance or poor absorption (often related to an insufficient
time interval between drug intake and food ingestion). (See "Use of biochemical markers of bone
turnover in osteoporosis", section on 'Osteoporosis therapy'.)
This approach (with markers of bone resorption) is only useful with antiresorptive therapy, not with
recombinant parathyroid hormone (PTH) (markers would increase). The approach to monitoring
patients on recombinant PTH therapy is discussed separately. (See "Parathyroid hormone therapy for
osteoporosis", section on 'Monitoring'.)
Bone mineral density Some [105-108], but not all [109], studies suggest that changes in bone
mineral density during therapy correlate with reduction in fracture risk. In one study, the greatest
fracture reduction occurred in those who gained BMD, although those with stable BMD still had fewer
fractures than those who lost BMD [105]. A meta-analysis of 12 clinical trials concluded that
improvement in spine bone mineral density accounts for a predictable but small part of the reduction
in fracture risk [110].
Serial BMD measurements are often performed to assess the clinical response to therapy. BMD that
is stable or improving is evidence for a treatment response. In order for a change in bone mineral
density to be considered significant, it should be greater than the "least significant change" (LSC) for
the densitometer in question. (See"Overview of dual-energy x-ray absorptiometry", section on
'Precision assessment'.)
The finding of a BMD decrease greater than the LSC in a treated patient should trigger additional
evaluation for contributing factors, which may include poor adherence to therapy, inadequate
gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a
disease or disorder with adverse skeletal effects [111,112]. Calcium and vitamin D supplementation
should be verified, and some evaluation for secondary causes of bone loss should be performed.
(See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women",
section on 'Evaluation'.)
If the patient is otherwise well and taking the drug and supplements correctly, the correct action is
controversial. Some clinicians believe that the decrease in BMD truly reflects a treatment failure and
would consider modification of the primary treatment for the osteoporosis. Others believe that the
decline in BMD does not necessarily imply inadequate therapy, but could be ascribed to
measurement error [113]. They would repeat BMD one year later, taking action only if the decline is
reaffirmed. When the decline in BMD is >5 percent, we usually switch from an oral bisphosphonate to
an intravenous bisphosphonate (typically zoledronic acid). The issues surrounding this decision and
the alternative treatment options are reviewed in more detail elsewhere. (See "The use of
bisphosphonates in postmenopausal women with osteoporosis", section on 'Response to therapy' .)
Guidelines There are several published guidelines for monitoring the response to osteoporosis
therapy; all recommend follow-up BMD (DXA) testing. However, there is no consensus on the optimal
frequency of monitoring and preferred site to monitor. The use of biochemical markers of bone
turnover for monitoring response to therapy has not been addressed in current guidelines, and there
are no prospective trials to define the most optimal approach for incorporating markers into monitoring
strategies [114]. (See "Bone physiology and biochemical markers of bone turnover" and "Use of
biochemical markers of bone turnover in osteoporosis".)
ISCD The International Society for Clinical Densitometry (ISCD) recommends follow-up BMD testing
(DXA spine and hip) when the expected change in BMD equals or exceeds the least significant
change (LSC), which is typically one to two years after initiation or change of therapy, with longer
intervals once therapeutic effect is established. In conditions associated with rapid bone loss, such as
glucocorticoid therapy, testing more frequently is appropriate [115].
NOF The National Osteoporosis Foundation recommends repeat BMD assessments (DXA spine or
hip) two years after initiating therapy and then every two years thereafter, with more frequent testing
in certain clinical situations [25].
AACE The American Association of Clinical Endocrinologists (AACE) recommends repeat DXA of
the lumbar spine (LS) and total hip every one to two years until stability is achieved, and every two
years or at less frequent intervals thereafter [116].
NAMS The North American Menopause Society (NAMS) recommends repeat DXA one to two years
after initiating therapy, and less frequently thereafter if BMD is stable [117].
Other A more conservative approach to monitoring takes the position that monitoring for efficacy of
antiresorptive therapy is unnecessary, as only a minority of patients continue to lose bone on therapy
[118]. This approach is used infrequently by clinicians but may be applicable to patients from remote
areas without access to medical facilities.
MEDICAL INTERVENTION AFTER FRACTURE In the United States and Europe, the majority of
patients who have had fragility fractures (or are at risk for fracture) do not subsequently receive
osteoporosis therapy [119-121], despite data demonstrating a beneficial effect in reducing the risk of a
second fracture.
The rates of testing and treatment for osteoporosis in patients with fragility fractures may be improved
by relatively simple interventions [122-125]. As an example, in a randomized, controlled trial of 272
patients over age 50 years with any distal forearm fracture, faxed reminders to clinicians (including
treatment guidelines) and patient education resulted in a threefold increase in the rate of osteoporosis
testing and treatment when compared with a control group receiving standard care [122]. However, in
another randomized trial, intervention to improve osteoporosis treatment after fracture was not
successful [126]. In addition, even when the interventions are reported to be effective, overall long-
term treatment rates for osteoporosis remain low.
There are few trials evaluating the initiation of bisphosphonates in the immediate post fracture period.
In most patients, a recent fracture should not preclude use of bisphosphonates, which can be initiated
within four to six weeks post fracture as long as the patient is able to sit upright for at least 30 minutes
(oral bisphosphonates). This topic is reviewed elsewhere. (See "The use of bisphosphonates in
postmenopausal women with osteoporosis", section on 'Use immediately after fracture'.)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The
Basics and Beyond the Basics. The Basics patient education pieces are written in plain language,
at the 5
th
to 6
th
grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10
th
to 12
th
grade reading
level and are best for patients who want in-depth information and are comfortable with some medical
jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on patient info and the keyword(s) of interest.)
Basics topics (see "Patient information: Osteoporosis (The Basics)" and "Patient information:
Calcium and vitamin D for bone health (The Basics)" and "Patient information: Medicines for
osteoporosis (The Basics)")
Beyond the Basics topics (see "Patient information: Osteoporosis prevention and treatment
(Beyond the Basics)" and "Patient information: Calcium and vitamin D for bone health (Beyond
the Basics)")
SUMMARY AND RECOMMENDATIONS
Lifestyle measures
We suggest adequate calcium and vitamin D for all postmenopausal women with osteoporosis
(Grade 2B). (See 'Lifestyle measures' above.)

In general, we suggest 1200 mg of elemental calcium daily, total diet plus supplement, and 800
international units of vitamin D daily. Some patients require additional vitamin D
supplementation. (See "Calcium and vitamin D supplementation in osteoporosis".)
Important additional lifestyle measures include exercise, smoking cessation, counseling on fall
prevention, and avoidance of heavy alcohol use for all postmenopausal women with
osteoporosis.
Recommendations for calcium and vitamin D supplementation as well as other lifestyle measures for
postmenopausal women without osteoporosis are found elsewhere. (See "Prevention of
osteoporosis", section on 'Summary and recommendations'.)
Pharmacologic therapy
In addition to nonpharmacologic therapy, we recommend that postmenopausal women with
established osteoporosis (T-score -2.5) or fragility fracture (hip or vertebral) be treated with a
pharmacologic agent (Grade 1A). (See 'Pharmacologic therapy' above.)
For the treatment of high risk postmenopausal women with T-scores between -1.0 and -2.5, we
also suggest pharmacologic therapy (Grade 2B). A reasonable cut point that may be cost-
effective in some settings is a 10-year probability of hip fracture or combined major osteoporotic
fracture of 3.0 or 20 percent, respectively. (See 'Candidates for therapy' above.)
For the treatment of osteoporosis in postmenopausal women, we suggest bisphosphonates as
first-line therapy (Grade 2B). (See 'Bisphosphonates' above and "The use of bisphosphonates in
postmenopausal women with osteoporosis".)

We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and
the availability of long-term safety data. (See 'Choice of drug' above.)
For most postmenopausal women with osteoporosis, we
suggest alendronate or risedronate over oral ibandronate (Grade 2B). (See 'Choice of
drug' above.) Oral ibandronate may be more convenient for patients, but a reduction in hip
fracture risk has not been established in randomized trials.
We suggest an intravenous bisphosphonate formulation for patients who cannot tolerate oral
bisphosphonates, who have difficulty with dosing requirements, including an inability to sit
upright for 30 to 60 minutes, or who have relative contraindications to bisphosphonates
(achalasia, scleroderma esophagus, esophageal strictures) (Grade 2B). Zoledronic acid is the
only intravenous bisphosphonate that has demonstrated efficacy for fracture prevention and is,
therefore, our agent of choice. (See "The use of bisphosphonates in postmenopausal women
with osteoporosis".)

Denosumab is an alternative option for patients who cannot tolerate oral bisphosphonates or
who have difficulty with the dosing requirements and have impaired renal function.
(See "Denosumab for osteoporosis".)
We suggest raloxifene for postmenopausal women with osteoporosis (low bone mineral density
[T score <-2.5] and no fragility fractures) who cannot tolerate or are not candidates for any
bisphosphonates (Grade 2B). (See "Selective estrogen receptor modulators for prevention and
treatment of osteoporosis".) Recommendations regarding raloxifene for the prevention of
osteoporosis are discussed separately. (See "Prevention of osteoporosis", section on 'Selective
estrogen receptor modulators (SERMs)'.)

Denosumab is also an option for such patients who are intolerant of or unresponsive to any
bisphosphonates. (See "Denosumab for osteoporosis".)

Strontium ranelate is also an alternative (where available) for patients who cannot tolerate any
bisphosphonates. (See 'Strontium ranelate' above.)
We suggest parathyroid hormone (PTH therapy) for postmenopausal women
with severe osteoporosis (low bone mineral density [T score <-2.5] and at least one fragility
fracture) who are unable to tolerate any of the available bisphosphonates (Grade 2B).
(See "Parathyroid hormone therapy for osteoporosis".)
In postmenopausal women with severe osteoporosis (low bone mineral density [T score <-2.5]
and at least one fragility fracture) who continue to fracture after one year of bisphosphonate
therapy, we suggest discontinuing the bisphosphonate and switching to human recombinant
PTH therapy (Grade 2B). (See "The use of bisphosphonates in postmenopausal women with
osteoporosis", section on 'Response to therapy' and "Parathyroid hormone therapy for
osteoporosis".)

Other candidates for parathyroid hormone are postmenopausal women with osteoporosis who
are unable to tolerate bisphosphonates, or who have relative contraindications to
bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures), in addition to
relative contraindications to selective estrogen receptor modulators (SERMs) (thrombosis, hot
flashes), or for whom other osteoporosis therapies fail (fracture with loss of bone mineral density
[BMD] in spite of compliance with therapy). (See 'Parathyroid hormone' above and "Parathyroid
hormone therapy for osteoporosis".)
Monitoring There is no consensus on the optimal strategy for monitoring patients on therapy.
However, we use the following approach:
For patients starting on therapy, we obtain a follow-up dual-energy X-ray absorptiometry (DXA)
of the hip and spine after two years, and if BMD is stable or improved, less frequent monitoring
thereafter. (See 'Our approach' above.)
For patients with conditions that might interfere with drug absorption or efficacy or for patients
who are reluctant to take anti-osteoporosis medications regularly, we typically measure fasting
urinary N-telopeptide (NTX) or serum carboxy-terminal collagen crosslinks (CTX) before and
three to six months after starting bisphosphonates or other antiresorptive therapy. If the marker
has not decreased by 50 (NTX) or 30 (CTX) percent, noncompliance or poor absorption, often
related to an insufficient time interval between drug intake and food ingestion, should be
considered.

This approach (with markers of bone resorption) is only useful with antiresorptive therapy, not
with recombinant PTH (markers would increase). (See "Parathyroid hormone therapy for
osteoporosis", section on 'Monitoring'.)