Archives of Osteoporosis (2021) 16:102

https://doi.org/10.1007/s11657-021-00954-1

POSITION PAPER

The Indian Society for Bone and Mineral Research (ISBMR) position
statement for the diagnosis and treatment of osteoporosis in adults
Sanjay K. Bhadada1 · Manoj Chadha2 · Usha Sriram3 · Rimesh Pal1 · Thomas V. Paul4 · Rajesh Khadgawat5 ·
Ameya Joshi6 · Beena Bansal7 · Nitin Kapoor4 · Anshita Aggarwal8 · Mahendra K. Garg9 · Nikhil Tandon5 ·
Sushil Gupta10 · Narendra Kotwal11 · Shriraam Mahadevan12 · Satinath Mukhopadhyay13 · Soham Mukherjee1 ·
Subhash C. Kukreja14 · Sudhaker D. Rao15 · Ambrish Mithal16

Received: 29 December 2020 / Accepted: 26 April 2021

© International Osteoporosis Foundation and National Osteoporosis Foundation 2021

Abstract
Summary The Indian Society for Bone and Mineral Research (ISBMR) has herein drafted clinical practice guidelines for
the diagnosis and management of osteoporosis for the people of India. Implementation of the position statement in clinical
practice is expected to improve the overall care of patients with osteoporosis in India.
Purpose In India, osteoporosis is a major public health problem. However, in the absence of any robust regional guidelines,
the screening, treatment, and follow-up of patients with osteoporosis are lagging behind in the country.
Methods The Indian Society for Bone and Mineral Research (ISBMR), which is a multidisciplinary group of physicians,
researchers, dietitians, and epidemiologists and who study bone and related tissues, in their annual meeting, drafted the guide-
lines for the diagnosis and management of osteoporosis that would be appropriate in a resource constraint setting like India.
Results Diagnosis of osteoporosis can be made in a patient with minimal trauma fracture without the aid of any other diag-
nostic tools. In others, bone mineral density measured by dual-energy X-ray absorptiometry remains the modality of choice.
Data indicates that osteoporotic fractures occur at an earlier age in Indians than in the West; hence, screening for osteoporosis
should begin at an earlier age. FRAX can be used for fracture risk estimation; however, it may underestimate the risk of future
fractures in our population and still needs validation. Maintaining optimum serum 25-hydroxyvitamin D levels is essential,
which, in most cases, would require regular vitamin D supplementation. Pharmacotherapy should be guided by the presence/
absence of vertebral/hip fractures or the severity of risk based on clinical factors, although bisphosphonates remain the first
choice in most cases. Regular follow-up is essential to ensure adherence and response to therapy.
Conclusions Implementation of the position statement in clinical practice is expected to improve the overall care of patients
with osteoporosis in India.

Keywords Osteoporosis · Fracture prevention · Guidelines · ISBMR · India

Introduction contribute significantly to morbidity and increased mortality.

As the population worldwide is aging, a significant increase
Osteoporosis is a condition characterized by low bone mass in the incidence of osteoporosis is expected. Approximately
and micro-architectural deterioration of bone tissue, with a 30% of all postmenopausal women have osteoporosis in the
consequent increase in bone fragility and susceptibility to USA and Europe. At least 40% of these women and 15–30%
fracture. Osteoporosis increases the risk of incident fragility of men will sustain one or more fragility fractures within
fractures. Fragility fractures are a major health concern that their remaining lifetime. In other words, 1 in 3 women over
age 50 will experience osteoporotic fractures, as will 1 in 5
men over age 50 [1, 2]. Despite marked advances in diagno-
* Sanjay K. Bhadada
[email protected] sis and treatment for osteoporosis, very few patients receive
appropriate treatment, even after a fragility fracture [3].
* Ambrish Mithal
[email protected] India is home to more than 1.3 billion people, with
approximately 230 million Indians over 50 years. Most data
Extended author information available on the last page of the article

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on the prevalence of osteoporosis among women in India Table 1  Summarizing the points that the expert committee have con-
come from studies conducted in small groups spread across sidered while drafting the consensus
the country, and estimates from 2015 have suggested that Risk factors for osteoporosis
20% of the 230 million Indian women over age 50 have Diagnosis of osteoporosis
osteoporosis [4, 5]. Prevalence of osteoporosis ranging Indications for treatment
from 8 to 62% in Indian women of different age groups has Pharmacological management of osteoporosis
been reported in several studies [6–14]. The prevalence of Follow-up for patients with osteoporosis
osteoporosis in males older than 50 years is also variable,
ranging from 8.5 to 24.6% [9, 15, 16]. A 2001 study in expa-
triate Indians in Singapore showed that the incidence of hip
fracture in the Indian population was 361 for women and
128 for men per 1,00,000 population. Extrapolating these Table 2  Summarizing the non-modifiable and modifiable risk factors
for primary osteoporosis
observations for the current Indian population as a whole,
the number of hip fractures every year would be more than Non-modifiable risk factors Modifiable risk factors
440,000, with a female to male ratio of about 3:1, with a
Age Nutrition
projected incidence of more than 600,000 in 2020 and over
Sex Calcium intake
1 million in 2050.
Ethnicity Vitamin D intake
Urbanization appears to be associated with an increased
Genetics Lifestyle factors—
prevalence of osteoporosis due to lifestyle habits such as smoking, alcohol,
sedentary lifestyle, increased indoor living, and lower sun exercise
exposure [4]. The awareness of osteoporosis is low in India, Peak bone mineral density Use of medications
with surveys indicating that only 10–15% of Indians are
aware of the disease [17]. According to the International
Osteoporosis Federation, the availability of dual-energy
X-ray absorptiometry instruments (DXA), a key tool for
diagnosing osteoporosis, is about 0.26 per million in India, Risk factors for osteoporosis
far below the recommended number of 10.6 per million [18].
Moreover, most of the DXA instruments are located in urban Various risk factors that contribute to postmenopausal osteo-
areas, and even many large cities in India do not have DXA porosis are broadly classified as non-modifiable or modifi-
facilities. Furthermore, the fact remains that the cost of DXA able risk factors and have been summarized in Table 2.
and osteoporosis treatments are largely not covered by insur- Non-modifiable risk factors include sex, age, ethnicity,
ance. Indians fare poorly compared to the more developed and genetics. Women have a smaller body frame size, and
Asian countries like Japan and Korea, where availability of in a developing country like India, are more likely to have
DXA is much higher (20.8 and 24.5 per million, respec- lower consumption of calcium-rich foods and inadequate
tively) [19]. Besides, only 20% of patients with osteoporosis sunlight exposure because of cultural or secular reasons.
are diagnosed and treated in India [20]. Even then, the treat- Furthermore, estrogen deficiency resulting from meno-
ment compliance rate is only around 64% [20]. pause contributes in a significant way to the development
Apart from the fact that osteoporosis is often asympto- of osteoporosis. Although the average age at menarche in
matic (until the patient sustains a fracture), and its treatment Indian girls is ~ 12.5 years, the average age at menopause
is usually life-long and costly, the lack of a definite local is 46.2 years which is earlier than that seen in non-Indian
consensus guideline makes management of osteoporosis in women [22], and this is a significant risk factor for the devel-
India even more difficult. The Indian Menopause Society opment of osteoporosis in Indian women [13, 23]. Numerous
published clinical practice guidelines on postmenopausal studies have reported increasing prevalence of osteoporosis
osteoporosis in 2013 [21]; however, new guidelines need to with advancing age, and this trend has been observed to a
be formulated based on recent clinical evidence. great extent among Indian women compared to men [9, 13].
The Indian Society for Bone and Mineral Research Genetic factors, race, and ethnicity also have a major
(ISBMR), which is a multidisciplinary group of physicians, influence on peak bone mass attainment. Asian Indian
researchers, dietitians, and epidemiologists and who study women have been shown to have 5–15% lower bone min-
bone and related tissues, in their annual meeting, drafted the eral density (BMD) than non-Asian women [24–26]. Also,
guidelines for the diagnosis and management of osteoporosis polymorphisms in the gene for vitamin D receptors in dif-
that would be appropriate in a resource constraint setting ferent races have been suggested to contribute to the ethnic
like India. The position paper has been discussed under the differences in BMD [4, 27, 28].
heads, as summarized in Table 1. Modifiable risk factors include the following:

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1. Nutritional factors: Calcium and vitamin D, the two pri- index (BMI) and BMD [37, 38]. Sarcopenia has also
mary nutrients involved in bone health, play a major role been shown to be associated with low BMD [39].
in influencing the risk of osteoporosis. 3. Other lifestyle factors: Urbanization has resulted in
a sedentary lifestyle, decreased exposure to sunlight
a. Calcium: Calcium in the form of hydroxyapa-
(sometimes from traditional clothing use), and low
tite crystals is deposited in the bone matrix and is
physical activity, which are detrimental to bone health
responsible for bone hardness. Calcium is obtained
[18]. Physical exercise, especially weight-bearing exer-
from the diet through dairy as well as non-dairy
cise, helps to improve and maintain muscle and bone
sources. The bioavailability of calcium from dairy
strength and also helps to improve body balance [21].
sources is much higher than non-dairy sources.
Lack of exercise is significantly associated with lower
Several studies have reported that Indian diets do
BMD in Indian women [38].
not meet the recommended dietary allowances of
  While being a major risk factor for osteoporosis,
600 mg/day of calcium for adult women as recom-
cigarette smoking is low among Indian women to be
mended by the Indian Council of Medical Research
a significant risk for osteoporosis [23]. Heavy drinkers
[29]. Indian diets are predominantly vegetarian,
have approximately a 1.7-times greater risk for osteo-
and the contribution of dairy products to the overall
porosis than light drinkers [40]. However, the DeVOS
calcium intake is minimal in the lower socioeco-
study reported that neither cigarette smoking nor alcohol
nomic classes. Furthermore, the unequal distribu-
consumption was common in Indian women and was not
tion of milk and milk products, with boys and men
significantly associated with prevalent fractures [36].
being served larger portions, is another factor that
  Recent data suggest that type 1 (T1D) and type 2 dia-
worsens the situation [5]. According to Harinarayan
betes mellitus (T2D) are significant risk factors for frac-
et al., Indian diets have a higher ratio of phytates
tures. Bone mineral density tends to be low in patients
to calcium, especially among rural Indians [30].
with T1D, BMD may be normal in patients with T2D,
Phytates may hinder calcium absorption from the
and yet, the fracture risk is increased, reflecting poor
already calcium-deficient diets. A survey conducted
bone quality in these patients. It is not known whether
in 2011–2012 in India reported a dietary calcium
better control of diabetes mitigates the increased fracture
intake of only 429 mg/day [31].
risk.
b. Vitamin D: Vitamin D is synthesized in the human
4. Medication use: Long-term over-the-counter glucocorti-
skin upon exposure to sunlight. Although there is
coid use [41] and minimum use of hormone replacement
no dearth of sunlight in India, several reports have
therapy (HRT) in the Indian scenario are a predominant
shown that Indians suffer from vitamin D deficiency
cause of osteoporosis. In addition, use of proton pump
[32–34]. Some of the reasons for vitamin D defi-
inhibitors and anticonvulsants have also been associated
ciency among Indians may be lower sun exposure
with low BMD and osteoporosis [42–44].
due to indoor lifestyle, traditional clothing lead-
ing to less skin exposure to sunlight (saris, salwar-
kameez, etc.), inadequate dietary intake, poor vita-
Diagnosis of osteoporosis
min D fortification of foods, and darkly pigmented
skin and atmospheric pollution [18, 35]. Vitamin D
Clinical
deficiency results in ineffective calcium absorption
from the gut, which in turn affects the mineralization
Any adult with a fragility fracture should be suspected of
of bones. The findings of the Delhi Vertebral Osteo-
having underlying osteoporosis (primary vs. secondary). In
porosis Study (DeVOS) from India suggest that the
addition, historical height loss of more than 4 cm in post-
odds of having osteoporotic fractures in subjects
menopausal women raises the possibility of asymptomatic
consuming calcium and vitamin D supplements are
vertebral fractures [45]. Individuals with persistent back
lower [36].
pain may have underlying vertebral fractures as well.
2. Nutritional status: Poor nutritional status is also a major
Dual‑energy X‑ray absorptiometry
contributing factor for osteoporosis, especially in India.
Bodyweight lower than 60 kg significantly increases the
Dual-energy X-ray absorptiometry, or DXA, is the most
risk of osteoporosis in women [23]. Several pathways
commonly used technique for measuring BMD. Although
link body weight and bone, and both lean and fat masses
true density measurement is 3-dimensional, DXA is a two-
are determining factors for BMD. Various studies have
dimensional measurement and thus calculates areal bone
demonstrated a positive correlation between body mass
density [46]. We recommend against the use of quantitative

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ultrasound (QUS) for screening or initial decision-making indications from the National Osteoporosis Foundation
regarding treatment of osteoporosis. (NOF) can be adopted for DXA measurement recommen-
Bone mineral density values are calculated in grams per dations [54]. Since data indicates that osteoporotic frac-
­cm2 (or area of bone density). In order to account for the dif- tures occur at an earlier age in Indians than in the West, we
ferences across DXA equipment across different manufac- recommend screening at an earlier age [5, 55].
turers, the values are further expressed in standard devia-
tions (SD) units from the mean BMD value of the reference • Women aged 60 and older and men aged 65 and older,
population [47]: regardless of clinical risk factors
• Postmenopausal women younger than 60 years and men
• “T” score of an individual is the number of SD his/her aged 50–64 years when there are concerns for osteopo-
BMD deviates from the mean BMD of 20–29-year-old rosis based on their clinical risk factor profile
reference population (usually Caucasian women—see • Women in the menopausal transition if there is a spe-
further discussion below). cific risk factor associated with increased fracture risk,
• “Z” score of an individual is the number of SD his/her such as low body weight, prior low-trauma fracture, or
BMD deviates from the mean BMD of the same age, high-risk medication
gender, and ethnic group reference population. • Individuals who have had a fragility fracture before the
age of 50 years
Whether the reference population should be matched for • Individuals with a condition (e.g., rheumatoid arthri-
sex and ethnicity is a matter of debate [48]. Most of the data tis, diabetes mellitus, malabsorption syndrome) or who
on fracture/BMD relationship has been derived using young are taking medication (e.g., glucocorticoids in a daily
Caucasian women as the reference population. The 2019 dose ≥ 5 mg prednisone or equivalent for ≥ 3 months)
International Society for Clinical Densitometry (ISCD) Offi- associated with low bone mass or bone loss
cial Position recommends the use of a uniform Caucasian • Any individual being considered for pharmacologic
(non-race adjusted) female normative database for women therapy for osteoporosis
of all ethnic groups. It also states that manufacturers should
continue to use NHANES III data as the reference standard
for femoral neck and total hip T-scores [49]. Biochemical investigations
Although normative data on BMD in healthy Indian
adults exist [9, 50, 51], at present, there is insufficient data Biochemical investigations should be directed at identi-
to assess the fracture risk using the Indian BMD reference fying the underlying cause of osteoporosis. In patients
database. Hence, for all practical purposes and in line with with osteoporosis, prior to initiation of pharmacotherapy,
the 2019 ISCD Official Position, the Caucasian female data- a basic biochemical and hormonal profile that includes
base derived from the NHANES III is used as India’s refer- serum calcium, phosphorous, total alkaline phosphatase,
ence population for calculating T-scores [52]. With regard to creatinine, 25-hydroxyvitamin D, and intact parathyroid
males, the 2019 ISCD Official Position recommends the use hormone (iPTH) would be desirable [56]. In patients with
a uniform Caucasian (non-race adjusted) female reference secondary osteoporosis, detailed blood investigations
for men of all ethnic groups; nevertheless, most manufactur- should be pursued based on clinical suspicion (Table 3).
ers continue to use the young male Caucasian database as
the reference population.
The purpose of measuring BMD with DXA is to identify Bone turnover markers
individuals at risk of developing future fractures so that pre-
ventative strategies can be employed. In addition, changes in Bone turnover markers (BTMs) are dynamic parameters
BMD measurements over time may be of value in determin- that reflect short-term, acute changes in bone remodeling
ing response to therapy. status that are not measured by BMD and hence, are com-
plementary to BMD measurement. However, BTMs have
Indications for DXA measurement no role in the diagnosis of osteoporosis. Although BTMs
are not routinely used to diagnose osteoporosis, they are
The number of available DXA scanners is limited in India, increasingly used in the follow-up of patients who are on
with only 0.26 scanners for 1 million population [18]. This anti-osteoporotic treatments. Hence, wherever available,
necessitates a judicious use of DXA facilities. Simultane- patients contemplating anti-osteoporotic therapy can get a
ously, there is a dearth of adequate utilization of DXA baseline BTM level estimated prior to initiation of therapy
by specialties treating individuals at risk for osteoporosis for subsequent comparison during follow-up [57].
in India [53]. Accordingly, as a trade-off, the following

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Table 3  Summarizing the biochemical investigations recommended by the expert committee to delineate the underlying cause of osteoporosis
Mandatory tests to be done in all patients with Specific tests to be done in suspected secondary osteoporosis
osteoporosis

Complete blood count Erythrocyte sedimentation rate and serum electrophoresis for suspected multiple myeloma
Total calcium IgA tissue-transglutaminase antibody (IgA tTg) in suspected celiac disease
Inorganic phosphate Serum testosterone (in men) and estradiol (in women) in suspected hypogonadism
Total alkaline phosphatase Overnight dexamethasone suppression test in suspected Cushing’s syndrome
Kidney function test Fasting blood glucose, post-prandial blood glucose and glycated hemoglobin in a known
or suspected case of diabetes mellitus
Liver function test
25-hydroxyvitamin D
Intact parathyroid hormone
TSH

Indications for treatment to suggest that individuals presenting with hip or spine frac-
tures if treated appropriately for osteoporosis have signifi-
The decision to initiate anti-osteoporotic treatment should be cant reductions in future risk of a recurrent fracture.
based on clinical screening tools such as fracture risk assess- Based on previously published literature, it is evident
ment tool (FRAX) and imaging, including DXA scan or that a recent fracture (within the past 2 years) is a good
plain radiography. FRAX is an online tool that assesses the predictor of imminent fracture risk in the near future [62,
10-year fracture risk of major osteoporotic fractures (wrist, 63]. This holds true for recent vertebral fractures [64] and
vertebral, hip, and shoulder) based on various risk factors. non-vertebral fragility fractures such as wrist and humerus
FRAX thresholds for initiating anti-osteoporotic treatment fractures [65]. Pharmacological therapies should be started
vary among different ethnicities [58]. The Endocrine Soci- in patients with recent fractures to prevent subsequent frac-
ety guidelines broadly recommend treating postmenopau- tures, but data on the optimal timing of initiation of therapy
sal women at high risk of fractures, especially those with a after a fracture are sparse. Based on the Horizon trial [61],
recent fragility fracture [59]. Nevertheless, the ultimate goal it is recommended to begin treatment at least 2 weeks after
of initiating treatment for management of osteoporosis is to a hip fracture.
reduce the burden of fragility fractures due to morbidity,
mortality, and associated costs. The key indications for ini- Indications of therapy based on bone mineral
tiating therapy for osteoporosis are summarized in Table 4. density

Clinical indications for initiating therapy Based on BMD, anti-osteoporotic treatment is indi-
cated in individuals over 50 years of age and with DXA
A clear clinical indication for starting treatment in post- T-score ≤ –2.5 at femoral neck, total hip, and lumbar spine.
menopausal women presenting with a major osteoporotic There is evidence that fracture risk is significantly reduced in
fracture (hip, spine, wrist, or humerus) that was found clini- these individuals following anti-resorptive or anabolic anti-
cally or on imaging. The presence of fracture is a better osteoporotic therapy [66, 67]. Treatment of osteoporosis
predictor of future fracture risk than T-score obtained by should be considered if lumbar spine, total hip, or femoral
DXA scan in such patients [60, 61]. There is strong evidence neck BMD T-scores are ≤  − 2.5.

Table 4  Summarizing the key indications for initiating anti-osteoporotic therapy

• A vertebral fracture (clinically apparent or found on vertebral imaging) or non-vertebral fracture (hip, wrist, and humerus)
• In individuals > 50 years of age with T-score ≤  − 2.5 at femoral neck or total hip or lumbar spine measured by DXA
• In individuals with osteopenia (T-score between − 1.0 and − 2.5 at the femoral neck or lumbar spine) with clinical risk factors or a 10-year
probability of a hip fracture ≥ 3.5% or a 10-year probability of a major osteoporosis-related fracture ≥ 10.5% based on the FRAX tool (based on
limited data in Indians)
• In individuals with type 2 diabetes mellitus, the intervention threshold should be increased to T-score ≤  − 2.0 at femoral neck or total hip or
lumbar spine measured by DXA [76]

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Among individuals with BMD below the expected range Pharmacological management
for age (BERA) and low bone mass (T-score between − 1.0 of osteoporosis
and − 2.5 at the femoral neck or lumbar spine), it is advis-
able to initiate treatment based on clinical risk factors or Fundamentals of osteoporosis management [77]
on an increased FRAX score. A FRAX score predicting
the 10-year probability of a hip fracture ≥ 3%, or a 10-year • Maintain serum 25-hydroxyvitamin D (25[OH]
probability of a major osteoporosis-related fracture ≥ 20%, D) ≥ 20 ng/mL in all patients with osteoporosis. How-
is indicative of an increased risk of fracture in the future. ever, we feel that a level of 30–40 ng/mL would be ideal.
Derivation of Indian-specific FRAX is based on the frac- • Supplement with vitamin D3 if needed; 1000 to 2000
ture risk in individuals living in Singapore and, therefore, international units (IU) of daily maintenance therapy
may not be fully applicable in the native Indian population. is typically required to maintain an optimal serum
Using the NOF treatment cut-off guidelines of 3% risk for 25(OH)D level in Indians.
hip fracture and 20% risk for MOF, Indian-specific FRAX • Higher doses of vitamin D may be necessary in the
may underestimate the fracture risk [68]. Based on studies presence of certain factors (e.g., obesity, malabsorp-
of Indian patients with hip fractures, these thresholds may tion, older individuals)
be lower, and studies are underway to define these lower • Counsel patients to maintain adequate dietary intake
treatment thresholds [58, 69]. However, more evidence is of calcium with a total intake (including diet plus
needed to support whether treatment initiation based on supplement, if needed) of at least 1000 mg/day for
these criteria truly results in absolute fracture risk reduc- women ≥ 50 years [3]
tion. Till conclusive data is available, it is prudent to use • Counsel patients to limit alcohol intake to no more than
white Caucasian database in clinical practice. 2 units per day
Trabecular bone score (TBS), a tool that assesses bone’s • Counsel patients to stop smoking
microarchitecture, has emerged as a valuable modal- • Counsel patients to maintain an active lifestyle, includ-
ity complementary to BMD [70, 71]. Recently, TBS has ing weight-bearing and balance exercises
revealed significant improvements in bone structure fol- • Provide counseling on reducing the risk of falls, par-
lowing administration of yearly zoledronic acid in a cohort ticularly among older patients
of Indian patients. A pan-India reference for TBS is under-
way [72]; however, therapeutic guidelines and thresholds
cannot currently be based on TBS [73]. Recommendations for initial first‑line therapy
for individuals with prevalent vertebral fractures

Role of other screening tools • Teriparatide is an effective anabolic agent to initi-

ate therapy in these cases, which to be continued for
Several other osteoporosis screening tools have been 24 months and followed by antiresorptives.
validated in both women and men in the Indian popula- • Intravenous zoledronic acid or denosumab are also
tion. These tools are based on simple clinical risk factors effective options. Since the protocol for discontinuing
and could be easily used in community settings [74]. In a denosumab is still not firmly established, zoledronic
large cohort of rural postmenopausal women, the SCORE acid is usually preferred as initial therapy for 3–5 years.
(Simple Calculated Osteoporosis Risk Estimation) screen- • Oral bisphosphonates can be used if the patient wants
ing tool was useful, with good sensitivity and good area to avoid injectable therapies.
under the curve for predicting femoral neck osteoporosis
on BMD measurement. It uses simple clinical risk factors
like age, weight, previous fracture, estrogen therapy, rheu- Recommendations for initial first‑line therapy
matoid arthritis, and ethnicity. A value ≥ 6 was found to for individuals with prevalent hip fracture
have good sensitivity and specificity for estimating risk in
the Indian population [75]. Similarly, the risk assessment • Intravenous zoledronic acid is the agent of choice in
tools OSTA (osteoporosis self-assessment tool for Asians) this group—it is recommended that hospitalized/post-
and MORES (male osteoporosis risk estimation score) surgical patients with hip fracture be given a dose of
have been validated for use in the Indian population [76]. intravenous zoledronic acid before being discharged
These tools are rapid, easy to perform, inexpensive, and from the hospital.
easily usable in the rural Indian setting, but the impact of • Denosumab is also an apt and effective choice but is often
initiating therapy based on thresholds derived from these used after zoledronic acid, for reasons explained above.
tools is not well studied.

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• While teriparatide can be used in this situation, there is Recommendations for the use of Hormone
limited data available in the prevention of hip fracture Replacement Therapy (HRT) in the management
[78]. of osteoporosis [79]

• Although effective in increasing bone mass and prevent

Recommendations for initial first‑line therapy fractures, HRT is not recommended for managing osteopo-
for high‑risk individuals without prevalent fractures rosis due to high risk of side effects such cardiac events and
breast cancer (although breast cancer risk is not increased
• Bisphosphonates are generally agents of choice for those
with estrogens alone). Hormone Replacment Therapy can
at high risk for fracture. While either weekly oral (alen- be used when there is an additional indication to use estro-
dronate, risedronate) or annual intravenous agents are gens such as uncontrollable menopausal symptoms. In
effective, concerns about compliance and ease of once select cases (within the first 10 years after menopause in
a year administration has made zoledronic acid the pre- women without contraindications), HRT can be used for
ferred drug for most patients. Both options should be prevention of postmenopausal osteoporosis.
discussed with the patient (weekly oral vs. annual intra- • Testosterone therapy may be added in androgen-deficient
venous) and treatment chosen accordingly. Denosumab men (testosterone level less than 200 ng/dL on more than
can be used as a first choice too if the patient reacts to or one determination) if accompanied by signs or symp-
wants to avoid bisphosphonates. Teriparatide can be con- toms of androgen deficiency (e.g., low libido, unex-
sidered for some with very low BMD (T score <  − 3.5) plained chronic fatigue, loss of body hair, hot flushes) or
and high risk of vertebral fracture. “organic” hypogonadism (due to hypothalamic, pituitary,
• The risk of rebound fractures is increased if subsequent
or specific testicular disorder). If testosterone treatment
doses of denosumab are not administered in time. does not alleviate symptoms of androgen deficiency after
3–6 months, it should be discontinued, and other thera-
Recommendations for initial first‑line therapies pies considered. It should be noted that anti-resorptive
for low and moderate risk cases for vertebral, and anabolic drug therapies are equally effective for
non‑vertebral, and hip fractures osteoporosis in men as well.

• Approved agents with efficacy to reduce hip, non-verte- Recommendations for the use of intranasal
bral, and spine fractures include alendronate, risedronate, calcitonin in the management of osteoporosis [59]?
zoledronic acid, and denosumab, and these are appropri-
ate as initial therapy for most patients at risk of fracture. • Intranasal calcitonin can be used for temporary bone pain
Often, oral bisphosphonates are preferred in low and relief.
moderate risk cases. • However, calcitonin’s effectiveness in prevention of
osteoporotic fractures is very limited and should there-
fore be prescribed only in women who cannot tolerate
Recommendations for the management bisphosphonates, denosumab, teriparatide, or raloxifene
of osteoporosis in chronic kidney disease patients or for whom these therapies are not considered appropri-
and those on haemodialysis ate.

• Management of patients with osteoporosis and chronic Recommendations for the use of combination
kidney disease (CKD) is difficult as bisphosphonates are therapies in the management of osteoporosis [79]
contraindicated in stage 4 and 5 kidney disease (eGFR
below 30 to 35 mL/min). Denosumab is not cleared by • Combination therapy can be considered in patients with
the kidney and therefore can be used in these patients. very high or imminent fracture risk [80]. The use of
However, the risk of hypocalcemia is high with this teriparatide and denosumab has been shown to result in
agent, especially in patients in stage 5 disease. Optimal a great increase in BMD as against either agent alone.
calcium intake and vitamin D status should be assured However, fracture prevention data are not yet available.
before starting denosumab.
• A major concern with antiresorptive therapy in patients Recommendations for the use of sequential
with CKD is dynamic bone disease and selected patients therapies in the management of osteoporosis [79]
should undergo undecalcified iliac bone biopsy if facili-
ties are available, to guide correct decision-making for • Treatment with teriparatide should always be followed
the management of osteoporosis. by antiresorptive agents to prevent bone density decline

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and loss of fracture efficacy. Either bisphosphonates or of treatment and regular follow-ups should be reinforced
denosumab can be used in this setting. and family members/caregivers should be actively involved
• In patients unresponsive to anti-resorptive therapy alone, in decision-making.
treatment can be followed by a combination of teripara-
tide and anti-resporptives [81]. Physical evaluation
• Treatment with denosumab, if it has to be discontinued,
should be followed by bisphosphonate, either zoledronate A short physical examination focusing on the patient’s
[82] or alendronate [83] in patients with adequate renal height should be undertaken. Other characteristics to assess
function. Delay in denosumab therapy or lack of an alter- include spinal tenderness, kyphosis, decreased spacing
nate therapy 6 months after last denosumab dose is asso- between lower ribs and pelvis, and oral hygiene. Patients on
ciated with a rebound increase in fractures. anti-resorptive therapy with poor dentition may be referred
to a dental physician for a detailed oral evaluation.

Follow‑up for patients with osteoporosis Biochemical evaluation

Treatment of osteoporosis with either anti-resorptive or Although no consensus exists, we recommend estimating
osteoanabolic therapy reduces the risk of incident fractures serum 25-hydroxyvitamin D at 6-month intervals for the
along with a subsequent reduction in morbidity and mor- initial 2–3 visits, and thereafter annually, to ensure vita-
tality. In a study assessing treatment algorithms in patients min D sufficiency while on treatment and target a serum
with osteoporosis in India, most clinicians preferred bis- 25-hydroxyvitamin D of at least 20 ng/ml.
phosphonates as the first line of therapy [84]. However, in Therapy with teriparatide is occasionally associated with
another study that aimed explicitly to evaluate the treatment hypercalcemia [67]. Serum calcium can be measured at least
adherence and compliance of postmenopausal osteoporotic 12 h after administering the first injection of teriparatide
women for different regimens of bisphosphonates in Indian because serum calcium levels can be transiently elevated
postmenopausal women, the authors found that an adherence within 6 h of injection. If a patient develops hypercalcemia,
rate of 56% was found with the monthly regimens, 36% for oral calcium intake should be reduced by 50% and serum
weekly regimens, and 32% for daily regimens [85]. Herein calcium repeated. If a patient develops persistent hypercal-
lies the paramount importance of continuous monitoring and cemia, calcium supplementation should be stopped, although
vigilant follow-up. discontinuation of teriparatide is rarely needed. An assess-
ment for other causes of hypercalcemia (e.g., hyperparathy-
Frequency of follow‑up roidism, malignancy, sarcoidosis, or hydrochlorothiazide)
should be undertaken simultaneously [86, 87].
There exists no consensus regarding the frequency of fol-
low-up for patients on anti-osteoporotic therapy. The first Radiology
follow-up can be planned after 3 months following initia-
tion of therapy. Thereafter, patients can be followed up at A new radiograph of the spine may be ordered at annual
3–6 monthly intervals for 2–3 subsequent contacts followed follow-up for all patients, particularly for patients complain-
by annual visits [21]. This promotes adequate adherence to ing of new-onset or worsening back-pain/kyphosis to rule
the treatment regime and reinforcement of fall prevention out any incident vertebral fractures. In addition, patients on
practices. bisphosphonate therapy complaining of thigh pain should
undergo a radiograph of the upper femur to rule out corti-
Clinical follow‑up cal beaking, the precursor of atypical femoral fracture [88].
Similarly, patients on anti-resorptive therapy with suspected
History osteonecrosis of the jaw should undergo a computed tomog-
raphy of the jaw to rule out the same.
At each visit, a brief history with an emphasis on assessing
new incident fractures, new-onset/worsening of kyphosis/ Bone mineral density
scoliosis, new-onset or worsening of back pain, and per-
ceptible height loss should be elicited. A history of falls is Treatments for osteoporosis increase BMD, but only mod-
a predictor of future falls and hence should be specifically estly. Evidence to support the use of BMD to monitor the
queried. Patients should also be asked about the possible treatment response is weak, but suggests that BMD can be
side effects of anti-osteoporotic therapy, notably, thigh and used for this purpose [89]. The latest Endocrine Society
jaw pain. At each and every visit, the need for continuation guidelines suggest monitoring of BMD by DXA at the spine

13
Archives of Osteoporosis (2021) 16:102 Page 9 of 13 102

and hip every 1–3 years to assess treatment response [59]. of robust data from India, an analogy can be drawn from
In the Indian scenario, repeating DXA every 1–2 years is the aforementioned guideline [95]. CTx and/or PINP can
recommended. It has been suggested that serial BMD meas- be used to evaluate patient adherence and drug responses
urements in treated patients may identify individuals who do to anti-resorptive agents, with measurements suggested
not adhere to treatment or have a secondary cause for bone at baseline, 3, 6, and 12 months after starting treatment.
loss. An increase in BMD above the least significant change Similarly, PINP can be used to evaluate patient adherence
(LSC) with treatment is good and is associated with a greater and drug responses to anabolic agents, with measurements
reduction in fracture risk than a stable BMD [90]. Usually, at baseline, 1 to 3 months, 6 months, and 12 months after
changes in lumbar spine BMD are more robust, while those starting anabolic treatment. A decrease in CTx by at least
at the hip are less dramatic, irrespective of the treatment 30% or by at least 100 ng/L from the pre-treatment value
modality used [91]. A stable BMD on treatment is also an is expected in a patient on anti-resorptive therapy [92, 96].
acceptable endpoint; however, a loss of BMD beyond the For PINP, a threshold of > 20% or > 10 μg/L from baseline
LSC (usually 5% in the lumbar spine, 4% in the total hip, is considered to be significant [92, 97, 98]. The above cut-
and 5% in the femoral neck) over 2 years suggests treatment offs, however, do not apply for combination and sequential
failure. In addition, having two or more fractures, especially therapies with anti-osteoporotic medications.
vertebral fractures, while on therapy also constitutes treat-
ment failure [92]. In such a case, low compliance, improper
dosing, vitamin D deficiency, celiac disease, multiple mye- Drug holiday
loma, concurrent glucocorticoid use, and endocrinopathies
(e.g., primary hyperparathyroidism, Cushing’s syndrome, The concept of a “drug holiday” has been proposed to
thyrotoxicosis, and unrecognized hypophosphatemic states) potentially reduce the incidence of the rare adverse events
should all be considered [59, 93, 94]. associated with long-term anti-resorptive therapy [99].
Assessing changes in BMD on serial follow-up measure- However, the recommendation for drug holidays is still a
ments requires careful attention to detail. Using the same matter of debate [100], especially since there is a dearth
scanner and a well-trained technologist who is aware of the of data from India. However, the Endocrine Society
pitfalls of bone densitometry can mitigate these problems. guidelines 2020 do recommend a drug holiday in selected
The provider responsible for reporting the results also needs groups of patients [59]. In patients on bisphosphonate
to be aware of assay limitations. Degenerative changes in the therapy, fracture risk needs to be evaluated after 3–5 years
spine or a new fracture in the region of interest may falsely (3 years for intravenous, 5 years for oral therapy). Patients
give the impression of BMD gain. with high-risk (defined as prior spine or hip fracture, or
a BMD T-score at the hip or spine of − 2.5 or below, or
Bone turnover markers 10-year hip fracture risk ≥ 3%, or risk of major osteo-
porotic fracture risk ≥ 20%) or very high risk of fracture
Bone turnover markers (BTMs) reflect the underlying bone (defined as multiple spine fractures and a BMD T-score at
turnover status. BTMs are dynamic parameters that can the hip or spine of − 2.5 or below) are not deemed eligible
reflect short-term/acute changes in bone that are often for drug holiday.
missed by BMD. Hence, BTMs reflect the therapeutic On the contrary, patients qualifying as having low risk
responses to anti-osteoporosis therapies much earlier than (defined as no prior hip or spine fractures, a BMD T-score
BMD, and therefore can be used in clinical practice, espe- at the hip and spine both above − 1.0, and 10-year hip frac-
cially to monitor compliance and adherence to treatment ture risk < 3% and 10-year risk of major osteoporotic frac-
[57]. The absolute values or the degree of change from tures < 20%) or moderate risk (defined as no prior hip or
baseline for BTMs can be used; considering the ethnic var- spine fractures, a BMD T-score at the hip and spine both
iations in BTMs and the pre-analytical variables involved above − 2.5, or 10-year hip fracture risk < 3% or risk of
in their measurement, using the degree of change rather major osteoporotic fractures < 20%) of fracture can be con-
than absolute values is more reasonable. Of the commer- sidered for drug holiday; however, fracture risk needs to be
cially available BTM clinical tests, the International Osteo- evaluated regularly at 2–4 year intervals, with therapy being
porosis Foundation (IOF) and the International Federation reinstituted if the patient falls into the high-risk category.
of Clinical Chemistry and Laboratory Medicine (IFCC) In patients on denosumab therapy, fracture risk needs to be
recommend using serum type I collagen C-telopeptide evaluated in 5–10 years. A drug holiday can be considered
(CTx) and serum procollagen type I N-propeptide (PINP). in low-moderate risk patients following a course of bispho-
A consensus statement on the use of BTMs for short-term sphonate with fracture risk being revaluated every 1–3 year.
monitoring of osteoporosis treatment in the Asia–Pacific There is no consensus on using BTMs to assess the need for
region has recently been published, and in the absence drug holiday [95].

13
102 Page 10 of 13 Archives of Osteoporosis (2021) 16:102

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Authors and Affiliations

Sanjay K. Bhadada1 · Manoj Chadha2 · Usha Sriram3 · Rimesh Pal1 · Thomas V. Paul4 · Rajesh Khadgawat5 ·
Ameya Joshi6 · Beena Bansal7 · Nitin Kapoor4 · Anshita Aggarwal8 · Mahendra K. Garg9 · Nikhil Tandon5 ·
Sushil Gupta10 · Narendra Kotwal11 · Shriraam Mahadevan12 · Satinath Mukhopadhyay13 · Soham Mukherjee1 ·
Subhash C. Kukreja14 · Sudhaker D. Rao15 · Ambrish Mithal16

1 10
Department of Endocrinology, Post Graduate Institute Of Department of Endocrinology, Sanjay Gandhi Postgraduate
Medical Education and Research, Chandigarh 160012, India Institute of Medical Sciences, Lucknow 226014, India
2 11
Department of Endocrinology, Parmanand Deepchand Department of Endocrinology, Army Hospital Research &
Hinduja Hospital, Mumbai 400016, India Referral, New Delhi 110010, India
3 12
Endocrinology and Diabetology Division, Voluntary Health Endocrinology Division, Sri Ramachandra Medical Center,
Services Hospital, Chennai 600020, India Chennai 600116, India
4 13
Department of Endocrinology, Christian Medical College, Department of Endocrinology, Institute of Post-Graduate
Vellore 632002, India Medical Education and Research, Kolkata 700020, India
5 14
Department of Endocrinology, All India Institute Of Medical Department of Medicine, University of Illinois, Chicago,
Sciences, New Delhi 110023, India IL 60612, USA
6 15
Endocrinology Division, Bhaktivedanta Hospital, Department of Internal Medicine, Division of Endocrinology,
Thane 401107, India Diabetes and Bone & Mineral Disorders, Henry Ford, Health
7 System, Detroit, MI 48202, USA
Endocrinology and Diabetes Division, Door to Care,
16
Gurgaon 122018, India Endocrinology and Diabetes Division, Max Healthcare,
8 New Delhi 110017, India
Department of Endocrinology, Dr. Ram Manohar Lohia
Hospital, New Delhi 110001, India
9
Department of Endocrinology, All India Institute Of Medical
Sciences, Jodhpur 342001, India

13