case study 79 osteoporosis

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Osteoporosis: A Step-by-Step Case-Based Study

Lokesh goyal.

1 Family Medicine, Christus Spohn, Corpus Christi, USA

Kunal Ajmera

2 Epidemiology and Public Health, Calvert Health Medical Center, Prince Frederick, USA

Osteoporosis is a common disease that affects our elderly population. This disease usually gets undiagnosed for an extended period. Osteoporosis increases the risk of fracture in our elderly population and increases morbidity. The cost associated with osteoporosis does carry a substantial burden in our society. Here, we present a case of osteoporosis with a fracture diagnosed in clinical settings. We discuss different etiology, pathophysiology, and treatment options available to treat this medical condition.

Introduction

Osteoporosis is a disease that causes a decrease in bone mass, increasing bone fragility and fracture [ 1 ]. Osteoporosis is a common disease, and it impacts one in three post-menopausal women and one in five men worldwide. There are roughly 200 million men and women who have osteoporosis in this world. The cost and morbidity associated with osteoporosis carry a substantial burden in our society. According to World Health Organization (WHO), a patient is diagnosed with osteoporosis if the Bone Mineral Density (BMD) T-score = -2.5 [ 1 - 3 ]. The test used to calculate the T score is also called the DXA scan. There are many instruments currently available that calculate the risk of fracture, one of them is called the Fracture risk algorithm (FRAX). FRAX calculates the risk of significant fractures (in ten years) like vertebral and hip fractures due to osteoporosis. FRAX can look at data provided by DXA and use it to predict the risk of fractures more accurately. In this case, we will focus on a patient who has osteoporosis. We will focus on etiology, pathophysiology and treatment options as well.

Case presentation

Patient X is a 62-year-old Caucasian female who presents to the outpatient clinic with right wrist pain and swelling following a fall on an outstretched hand in the garage at home. This patient has a past medical history of hypertension (HTN), chronic heart failure (CHF), pneumonia, chronic obstructive pulmonary disease (COPD), asthma, gastric ulcer, menopause (age 50), stooped posture, and vertebral bone fracture. The patient has a family history of CHF and HTN in her brother (age 55), a pelvic fracture in her mother (age 82), and the mother was also diagnosed with osteoporosis. The patient’s father has HTN. Patient X is married with four children and works in Walmart. She smokes one pack of cigarettes every day and occasionally drinks alcohol. She does no exercise and is fully mobile with no disabilities. The patient does not report symptoms of orthopnea, weakness, chest pain, palpitation, paroxysmal nocturnal dyspnea, or excessive bleeding. The patient is currently taking lisinopril for decreasing afterload; furosemide for reducing edema; atorvastatin for hypercholesterolemia; metoprolol for decreasing heart rate; omeprazole for stomach acidity; fluticasone for her asthma, and epidural steroid injection for lower back pain. Patient X reports to the clinic in acute distress and is oriented to time, person and place. The patient weighs 250 lbs., BP 145/88, pulse 90, and O 2 saturation level of 92%. The patient lungs were clear on auscultation bilaterally. The cardiovascular exam showed a regular rate and rhythm without any murmurs. The right wrist is swollen and hurts to move. There was no edema on the left hand or feet. Radial, femoral, and dorsal pedis pulses were normal bilaterally. The patient was sent to the hospital to get an X-ray of the right hand (Figure ​ (Figure1), 1 ), which revealed Colle’s fracture (distal radius) on the right hand. The hospital then puts a cast on the patient’s hand. The blood test was normal in this patient except for low levels of Vitamin D. The patient was also asked to get a DEXA scan, which revealed a T score of -2.9 (less than -2.5 is osteoporosis). The patient was started on bisphosphonates, raloxifene (selective estrogen receptor modulator [SERM]), and also given Vitamin D (1,000 mg) and calcium tablets. The patient was advised to start exercising daily and eat a healthy diet. She was also asked to be careful while walking.

Pathophysiology

The cause of osteoporosis [ 1 - 3 ] is an imbalance between bone formation and bone reabsorption. A typical bone is constantly being broken down and reformed. Around 10% of our total bone mass is under constant remodeling at any given time [ 4 ]. Due to menopause [ 5 , 6 ], the amount of estrogen secreted in a woman can decline rapidly [ 5 , 7 ]. The lack of estrogen [ 8 ] will increase the risk of bone reabsorption and decrease the deposition of new bone. Due to menopause, we also see an increase in basic multicellular units made of osteoclasts and osteoblasts cells. These osteoclast and osteoblast cells will sequentially resorb old bone and form new bone. This prolongs the osteoclast resorption time and relative shortening of the time for osteoblastic bone formation. The recent studies [ 6 , 9 , 10 ], both done in vitro and in vivo, show that, in the eugonadal state, estrogen will inhibit receptor activators of nuclear factor-κ B ligand (RANKL). RANKL [ 9 , 10 ] is a molecule found on the bone marrow stromal cells/osteoblast precursors and T and B cells. A decrease in the concentration of Vitamin D can also increase the risk of fracture and lower the BMD in the patient’s body. The primary source of Vitamin D comes from sunlight and diet. A severe deficiency of Vitamin D levels can lead to osteomalacia (in adults) or rickets (in children). These diseases cause softening of bones and increase the risk of fracture tremendously. The use of anti-acidity medications [ 2 ] like proton pump inhibitors (PPI) or H2 receptor blockers (Cimetidine) has been shown to increase fracture risk in adults. The increase in the risk of fracture due to anti-acidity medication is that these medications induce hypochlorhydria in the human body. This hypochlorhydria affects the absorption of calcium and therefore leads to a decrease in calcium in the body, increasing the risk of fracture. Any changes in sex hormones [ 8 ] are the most critical factor which affects bone loss due to aging; however, we still need to recognize the non-sex steroid hormonal changes that also occur in the human body. The most important hormone that affects bone physiology is the decrease in growth hormone secretion (as we age) from the pituitary gland. This decrease in growth hormone leads to a decrease in the production of insulin-like growth factors (IGF-1 and IGF-2) [ 4 - 6 ] from the liver. These hormones have a role in osteoblast activity and differentiation. A decrease in IGF is also associated with increased IGF inhibitory binding protein (IGFBP-2). An increase in IGFBP-2 in the human body leads to a decrease in BMD in adults [ 6 - 8 ].

The most pivotal step in the diagnosis of osteoporosis is a DEXA scan (dual-energy x-ray absorptiometry). This test measures BMD. T score of less than -2.5 is considered a diagnosis of osteoporosis. Whereas a score of -1 to -2.5 is considered osteopenia. The NOF guidelines [ 4 - 6 ] state that a patient should undergo osteoporosis treatment not just after a hip/vertebral fracture or with a T- score≤−2.5, but treatment should also be considered in postmenopausal women and men with osteopenia (age > 50). The main goal of osteoporosis treatment is not just to increase BMD but also to prevent fractures in the future. Calcium and Vitamin D deficiency leads to an increase in the risk of bone loss and muscle weakness. This deficiency will, in turn, increase the patient’s risk of falling and fracture. By prescribing calcium and Vitamin D supplements to the patient, we can decrease fracture risk by 10%-15%. Multiple outcomes of the raloxifene evaluation (MORE) [ 6 , 7 ] study has shown that raloxifene, a SERM, reduces the risk of vertebral fracture by 30% if used continuously for three years. National Institute of Health and Care Excellence (NICE) [ 6 , 7 ] recommends using raloxifene in postmenopausal women at increased risk for osteoporosis or women intolerant of Bisphosphonates. Bisphosphonate is the class of drugs used for preventing osteoporosis. It has been the best choice for the treatment of osteoporosis since the 1960s. Bisphosphonates and their analogs bind at sites where bone resorption and new bone formation occur. The osteoclasts will ingest bisphosphonates bound to the mineral and therefore inhibit the function of osteoclasts. This will consequently lead to inhibition of bone resorption.

In addition to her past medical history and family history, these findings put this patient at risk of fracture due to osteoporosis. The past medical history of patient X (menopause, steroid meds, and old age) is consistent with the common risk factors for the development of osteoporosis. Patient X also has a history of vertebral fracture, which is most likely to have been caused due to osteoporosis. The most pertinent physical exam findings for this patient are the presence of stooped posture, history of vertebral fracture, and chronic back pain. The most critical risk factor for fracture in the case of osteoporotic patients is an unstable gait, which increases the risk of falls and, therefore, fractures. To rule out any risk of future fractures, this patient went through a thorough examination (gait abnormalities, orthostatic hypotension, and cognitive impairment). Patient X also went through a thorough neurological examination to rule out any spinal cord or peripheral nerves being compromised. This patient was prescribed bisphosphonates and calcitonin, which will help in inhibiting the osteoclast function. Raloxifene (SERM), this drug, will help decrease the risk of vertebral fractures and breast cancer in women. Vitamin D and Calcium supplements will help in increasing the BMD in the bones and decrease the risk of osteoporosis. The patient was also asked to have a good diet and exercise daily to encourage weight loss. The patient must do some weight-bearing exercise as this helps increase the BMD and helps decrease osteoporosis. Due to an increase in fracture risk from falling, the patient was advised to use a walker while walking.

Conclusions

Through this case presentation, we realize that patients in our society are not appropriately screened for osteoporosis during their lifetime. This is usually due to a lack of medical knowledge among our patient population and sometimes the cost as well. Osteoporosis remains a public health problem and an economic burden to our society. As the incidence of osteoporosis continues to increase, it is clear that preventive interventions must be considered early on and sometimes as early as in utero. Patient education in primary care should focus on the benefits of a healthy lifestyle, a nutritious, and balanced diet (with Vitamin D and calcium supplements) in preventing the risk of osteoporosis. Patients must also avoid smoking, drinking, and illicit drugs as they have been shown to decrease the BMD and increase the risk of osteoporosis.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study

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Osteoporosis: Diagnosis and Management

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CASE STUDY 1

An Asian woman, Patient D, is 64 years of age with a history of type 2 diabetes, asthma, hypertension, and degenerative joint disease. She presents to a general medicine clinic with persistent lower back pain. The patient reports that for the last few months, she has been experiencing aching pain in the lower lumbar area. It is worse with exertion. The pain is fairly localized, without radiation. She does not experience any tingling, numbness, or weakness. There is no history of trauma. On exam, blood pressure is 135/75 mm Hg, heart rate 72 beats per minute, respirations 18 breaths per minute, temperature 99 degrees Fahrenheit, height 59 inches (150 cm), and weight 99 lbs (45 kg). The patient does exhibit some tenderness to palpation in the lower lumbar area. She notes that she tries to remain active, walking about 2 to 3 miles, three or four days a week; she is also a devoted gardener. She is concerned enough about this pain that she believes she needs an x-ray. She also reluctantly remarks that she is not sure if she is exaggerating, but she feels she might be "shrinking." She recently tried on a pair of pants she purchased several years ago, and now they appear to be too long. She wants to know if this is possible. One of her sisters recently told her that she was diagnosed with "brittle bones." She asks you what this means and if she should be concerned.

Patient D has numerous risk factors for osteoporosis, including older age, female gender, and low body weight. She may also have a family history, and this should be explored further. Upon review of her medications, she has been treated with steroids for exacerbation of asthma, but there have been no such episodes in the past year. In addition, she is not on estrogen replacement therapy. The use of steroids and estrogen deficiency may be additional risk factors. Her level of physical activity is encouraging, but it does not offset her numerous risk factors.

As noted, most often patients do not present with significant signs or symptoms of osteoporosis. In this example, Patient D does present with back pain in the lower lumbar area, which has been persistent for several months. The physical exam does not reveal any signs of radiculopathy, obvious fracture, nerve damage, or acute cause of the low back pain. In addition, the review of past records does demonstrate that Patient D is approximately 10 cm shorter in height than five years ago. She clearly needs a work-up for osteoporosis.

Patient D has a full chemistry panel including calcium and phosphorus, liver function tests, thyroid function tests, and a complete blood count (CBC). All are within normal limits. Normal values should not be unexpected in patients with osteoporosis, as this is often the case. Because suspicion remains high for osteoporosis, Patient D must undergo bone mineral density testing. Although the patient wishes to have an x-ray, simple x-rays would not be helpful here unless one is trying to rule out a fracture or other structural cause of the low back pain.

Patient D should undergo DXA of the hip. She has a history of degenerative joint disease, which makes spine-imaging results more difficult to interpret. In addition, she has numerous risk factors, which make DXA a preferred test.

Patient D's T-score from DXA of the hip is -2.5; she meets the WHO criteria for osteoporosis. Given that she is already experiencing symptoms, intervention is necessary. A review of diet is the first step. Patient D currently does not use any supplements because she believes she eats a healthy diet. However, further review with a dietitian reveals that she is below the recommended intake of calcium and vitamin D. Therefore, supplementation with both calcium and vitamin D should begin immediately. As noted earlier, Patient D tries to remain active, mostly involved in walking and gardening. These can be good aerobic exercises, depending on their intensity, and she should be encouraged to continue them. However, a weight-bearing exercise regimen should slowly be worked into her routine. Because she does have degenerative joint disease, a monitored exercise program should be initially pursued so that she focuses properly on form and does not cause any excess stress on her joints.

Medications should also be strongly considered, given her T-score as well as symptoms. SERMs and bisphosphonates should be the preferred medications. Estrogen replacement is not recommended.

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Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study

• Original Article
• Open access
• Published: 01 July 2024

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• Soichiro Kimura 1 , 2 ,
• Takashi Sunouchi 1 , 2 ,
• So Watanabe 2 , 3 ,
• Yoshitomo Hoshino 1 , 2 ,
• Naoko Hidaka 1 , 2 ,
• Hajime Kato 1 , 2 ,
• Shu Takeda 4 ,
• Masaomi Nangaku 1 ,
• Noriko Makita 1 , 2 ,
• Kotaro Azuma 2 , 3 ,
• Taro Kojima 3 ,
• Takehiro Matsubara 5 , 6 ,
• Taku Saito 2 , 5 &
• Nobuaki Ito   ORCID: orcid.org/0000-0002-4071-5372 1 , 2  

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Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them.

The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age.

Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022.

Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase , biomineralization associated ( ALPL ), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides.

If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

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Introduction

AtypicalPlease femoral fracture (AFF) is a type of fracture that develops with weak external forces or without trauma in the subtrochanteric area or shaft of the femur [ 1 ]. More than three cases per 1000 patient-years of treatment involve AFF in osteoporotic women who have taken antiresorptive agents continuously for more than 8 years. The risk of AFF among antiresorptive agent users with osteoporosis is approximately eightfold greater in Asian women than in Caucasian women [ 2 , 3 , 4 ]. Bisphosphonate use is a historically well-recognized risk factor for AFF, and there are now multiple recent case reports regarding AFF after denosumab in bisphosphonate-naive patients [ 5 , 6 , 7 , 8 , 9 ]. Glucocorticoids are also a candidate risk factor for AFF in osteoporotic women who take antiresorptives [ 10 , 11 ]. There are reports of the development of AFF after romosozumab treatment, although it is still unclear whether this treatment is associated with the development of AFF [ 12 ]. The incidence of AFF in people who have taken antiresorptive agents for skeletal metastasis for more than 1 year is more than 2%, perhaps because the cumulative annual absorbed dose of an antiresorptive agent in patients with cancer is about ten times greater than the cumulative annual absorbed osteoporosis dose [ 13 , 14 , 15 ].

More than one-third of patients with one AFF eventually develop contralateral AFF. The union of the AFF is often delayed, which places patients in adverse situations and suggests a slow healing response due to antiresorptive-based inhibition of Haversian remodeling, an underlying bone disease, or perhaps even a combination of the two [ 10 , 16 ].

Several metabolic bone diseases, such as hypophosphatemic osteomalacia, including X-linked hypophosphatemic rickets/osteomalacia (XLH), tumor-induced osteomalacia (TIO), Fanconi syndrome, and vitamin D-dependent rickets (VDDR), and several skeletal dysplasias, including hypophosphatasia (HPP) and osteopetrosis, are recognized to cause fractures that are morphologically identical to the AFF [ 17 , 18 , 19 , 20 , 21 ]. Several reports indicating that morphologic AFF is sometimes associated with monogenic bone diseases have been reported, and several genes, including ALPL , GGPS1 , COL1A2 , and CYP1A1 , have been identified as disease susceptibility genes by candidate-gene association studies and genome - wide association studies (GWASs) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].

The updated epidemiology of AFF and the high frequency of bilateral fracture and delayed union in AFF suggest the possible existence of conditions and unidentified bone disorders that are associated with low bone formation, including the disorders mentioned above. Thus far, few studies have explored latent metabolic bone disease and skeletal dysplasia comprehensively in patients with atypical femoral fractures in a single cohort. In the current study, we retrospectively collected and analyzed the clinical characteristics of 38 patients with subtrochanteric fractures to reveal the presence of known risk factors such as bisphosphonate and glucocorticoid use, along with latent bone metabolic disorders and skeletal dysplasia associated with low bone formation.

Participants

Data on the clinical characteristics, recognized risk factors for AFF, and disorders associated with low bone formation were collected retrospectively from the clinical records of all 38 patients aged 15 or older admitted to the Department of Orthopedic Surgery and Spinal Surgery and Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital between February 2012 and March 2022, with a diagnosis of subtrochanteric femoral fractures which are identical to the 2nd definition of AFF by ASBMR except for the inclusion of fractures among patients with already-recognized bone diseases [ 1 ].

Data collection

The following data were collected from each patient: age, date of diagnosis, height, weight, body mass index (BMI), laterality of subtrochanteric femoral fracture, past medical history, all past clinical fractures, past subtrochanteric femoral fractures, alcohol consumption, smoking, medication (specifically including bone modifying medications, such as antiresorptive agents, and glucocorticoids), plasma, serum, and urine laboratory data related to bone metabolism, and serum albumin (Alb), albumin adjusted calcium (cCa), inorganic phosphate (Pi), alkaline phosphatase (ALP), creatinine (Cre), γ-glutamyl transpeptidase (γGTP).

Biochemical measurements, including Alb, Ca, Pi, ALP, Cre, and γGTP, were assayed by JCA-BM8040 (JEOL, Tokyo, Japan) before May 2013 and LABOSPECT008 (Hitachi High-Tech, Tokyo, Japan), thereafter using the manufacturer’s standard reagents.

Statistical analysis

Continuous data are presented as medians (interquartile ranges), and categorical data are summarized as numerical values (%). Chi-square tests to identify risk factors other than age were performed in two patient groups divided by several cutoff ages to evaluate the influence of age as a risk factor for morphologic AFF. All the statistical analyses were performed with JMP Pro 16 (SAS Institute Japan, Tokyo, Japan).

Study approval

All procedures were performed following the ethical standards of the Declaration of Helsinki and were approved by the institutional ethical board of the University of Tokyo Hospital [Ref. 3820].

Characteristics of 38 patients

Clinical characteristics of 38 patients are presented in Table  1 . Among the 38 patients, 30 patients (79%) were female, 18 patients (47%) had past clinical fractures, six patients (16%) (patients #7, 12, 25, 26, 32, and 38) had past subtrochanteric fractures, and five patients (13%) (patients #7, 12, 25, 34, and 38) had subtrochanteric fractures on both sides (Table  2 ). Among the five patients who experienced subtrochanteric fractures on both sides, four patients (patients #7, 12, 25, and 38) had previous subtrochanteric fractures and developed new subtrochanteric fractures on the other side this time, while one patient (patient #34) developed incomplete bilateral subtrochanteric fractures simultaneously this time.

Laboratory data

The median serum Alb concentration was 3.4 g/dL, which was below the reference range (4.1–5.1 g/dL). The median serum Pi, cCa, Cre, and γGTP levels were within the reference ranges (Table  3 ). Among the 37 patients whose ALP could be obtained, ALP levels were within the reference interval in 30 patients and were lower and higher than the reference range in two and five patients, respectively. Among the two patients with low ALP, a 56-year-old male (patient #19) was suspected of being a carrier of a heterozygous ALPL variant due to mildly and continuously low serum ALP and a history of tibial fracture. There was another patient with low serum ALP levels (patient #13; the left endmost patient in Supplementary Fig.  1 ). He was treated with alendronate for 4 years, which was likely responsible for the low ALP level. Low ALP was observed only once on admission, so he was not suspected to be a carrier with a heterozygous loss-of-function variant for ALPL. Regarding the patients with high ALP levels, a 48-year-old female (patient #34) was diagnosed with TIO. One of the patients with high serum ALP levels (patient #8), who was in a wheelchair for 11 years due to complete paraplegia below Th10, was a 15-year-old male, and the ALP level was within the reference range for that age. Two patients (patients #28 and 35) showed high ALP levels, and at the same time, serum γGTP levels were also elevated; hence, liver dysfunction was probably the cause of high ALP levels. The other patient with persistently high ALP levels (patient #2) was retrospectively considered to have hypophosphatemic osteomalacia, but detailed differential diagnosis was difficult due to the lack of measurements for serum Pi.

The Venn diagram describes the number of age ≥ 75 years, antiresorptive agents (bisphosphonate or denosumab) users, and glucocorticoid users and their overlap in 38 patients who were diagnosed with subtrochanteric femoral fractures. Three out of 7 patients without these three risk factors were diagnosed with suspected carrier of heterozygous ALPL variant (patient #19), pycnodysostosis (patient #32), and TIO (patient #34), and the other two patients (patients #20 and 35) were treated with anticancer drugs

Potential risk factors

The most frequent risk factors were age ≥ 75 years, antiresorptive agents, and glucocorticoids when combined with antiresorptive agents (Table  2 ). Among the 18 patients with antiresorptive agents, 15 (83%) were treated with osteoporosis doses of bisphosphonates, one changed alendronate to denosumab (60 mg/6 months), and two were treated with denosumab (120 mg/month) for bone metastasis of breast cancer (Supplementary Table  1 ). All patients in the glucocorticoid category were treated with prednisolone, and no patient was administered intravenous glucocorticoid (Supplementary Table  2 ). Four patients were treated with anticancer drugs; three patients (patients #28, 35, and 37) had breast cancer and the other patient (patient #20) suffered from lung cancer (Supplementary Table  3 ). As shown in the Venn diagram created to evaluate the overlap trend of major risk factors, 12 out of 21 patients who are 75 years or older did not have any other risk factor. According to the chi-square test, in the group of 17 patients aged < 75 years and the group of 21 patients aged ≥ 75 years, the number of patients without any of the eight risk factors in Table  2 , except for age, were one (6%) and ten (48%), respectively ( p  = 0.0048). Similarly, there were one (6%) and ten (50%) patients in the respective groups with the cutoff age of 80 years was used ( p  = 0.0026) (Supplementary Table  5 ). The area under the curve (AUC) for the receiver operating characteristic (ROC) curve for predicting whether a patient had any risk factors other than age was 0.74, and the cutoff age with the maximum Youden’s index was 79 years (Supplementary Fig. 2 ). In contrast, 16 out of the 18 patients treated with antiresorptive agents had additional risk factors; likewise, nine of ten patients who used glucocorticoids also received antiresorptive agents for osteoporosis (eight: bisphosphonates, one: denosumab) (Fig.  1 ).

Bone metabolic disorders and skeletal dysplasia associated with low bone formation were diagnosed or suspected in four participants (patients #7, 19, 32, and 34). Three of these were among seven patients without the aforementioned major risk factors (patients #7, 18, 19, 20, 32, 34, and 35); two were diagnosed with pycnodysostosis (patient #32) and TIO (patient #34), and one was suspected to be a carrier of a heterozygous ALPL variant characterized by consistently low serum ALP (patient #19). Patient #32 had already been diagnosed with pycnodysostosis with a genetic test before the fracture. Pycnodysostosis is characterized by a low rate of bone remodeling and osteosclerosis. This low rate of bone remodeling is associated with a low bone formation rate, much like that found in patients who take antiresorptives [ 33 ]. It was noteworthy that three (patients #7, 19, and 34) of the four patients had not been diagnosed with or suspected of these disorders until the time they developed AFF. Clinical data of those four patients are presented in Supplementary Table  4 , and brief case reports are described in Supplementary Text 1 [ 34 ].

The associations of each risk factor with past clinical fractures, past subtrochanteric fractures and subtrochanteric fractures on both sides were investigated. The findings revealed that among four patients with diseases associated with low bone formation (hypophosphatemic osteomalacia and carriers of ALPL variants are associated with low bone mineralization), all four (patients #7, 19, 32, 34) had past clinical fractures, two (patients #7 and 32) had previous subtrochanteric femoral fractures, and two (patients #7 and 34) experienced subtrochanteric femoral fractures on both sides (Table  2 ).

AFF is a fracture that occurs on the subtrochanteric femur or shaft of the femur with minor external force or without trauma, and the detailed 2nd definition of AFF was introduced by ASBMR in 2013 [ 1 ]. A systematic review of 14 studies reported that the incidence of AFF was as low as 3.0 to 9.8 cases per 100,000 person-years [ 35 ], although the incidence of AFF in osteoporotic women who are treated with antiresorptive agents continuously for more than 8 years is more than three cases per 1000 patient-years of treatment [ 3 , 4 ].

Similar to the purpose of our current study, Nguyen et al. [ 17 ] conducted a literature review to determine the presence of monogenic disorders among patients with AFF. In this article, 2566 relevant citations were searched, and reports of 23 individuals with seven monogenic bone disorders (osteogenesis imperfecta, pycnodysostosis, HPP, X-linked osteoporosis, osteopetrosis, XLH, and osteoporosis pseudoglioma syndrome) were identified. In eight patients, monogenic disorders were uncovered after the development of morphologic AFF [ 17 ]. Similarly, in a literature review by Zhou et al., AFF was reported in 57 patients with monogenic bone diseases; 17.5% of those patients were diagnosed after the development of AFF and 56.1% had no history of antiresorptive treatment [ 36 ]. These studies not only point out that both antiresorptive agent and particular metabolic bone diseases/skeletal dysplasia are independently associated with morphologic AFF, but also raise the possibility that when both antiresorptive treatment and monogenetic bone diseases exist simultaneously in the same individual, their effects on AFF may be additive. In one report, 14 of 16 untreated osteoporosis patients with persistently low serum ALP levels had loss-of-function mutations in the ALPL gene [ 37 ]. The serum ALP level is a serological marker of overt osteomalacia, especially when it is persistently elevated; therefore, clinicians should consider serum ALP levels to help exclude typical metabolic bone disease/skeletal dysplasia before initiating antiresorptive agents for osteoporotic patients [ 37 , 38 ]. Based on serum ALP levels, two patients with metabolic bone disease/skeletal dysplasia were identified among four patients in the current cohort. However, in addition to serum ALP levels, detailed clinical examinations such as bone mineral density (BMD), past medical history, and medication history are necessary to thoroughly identify metabolic bone disease/skeletal dysplasia. The current study revealed that four out of 38 of the patients with morphologic AFF were suffering from definite and suspected bone diseases, and, notably, bone diseases were diagnosed or suspected only after the first morphologic AFF in three of them.

In this study, 16 out of 38 patients (42%) had a history of past bisphosphonate treatment. Bisphosphonate use is the most recognized risk factor for the development of AFF and the occurrence of AFF in osteoporotic women who have used antiresorptive drugs for more than 8 years is not uncommon [ 3 , 4 ]. The development of AFF has also been reported in patients treated with denosumab [ 5 , 6 , 7 , 8 , 9 , 39 ]. Although there is no definite evidence that anticancer drugs increase AFF, it has been reported that cyclophosphamide decreases osteoblasts and osteoclasts in mice, suggesting that particular anticancer drugs may suppress bone turnover in humans [ 40 ]. All 38 patients included in the current study were Japanese. Regarding racial differences, it has long been suggested that Asian race is a risk factor for AFF, and recently, Lo et al. reported that Asians were eight times more likely to develop AFF than non-Asians in a cohort in the USA, Nguyen et al. reported that Asians were 3.4 times more likely to develop AFF than non-Asians in a cohort in an Australian hospital, and Dhanekula et al. reported that Asian ethnicity increased the risk of developing AFF by sevenfold in an Australian multicenter cohort [ 2 , 41 , 42 ]. AFF risk is significantly greater in patients over age 65 than in those younger than age 65. In previous reports, the incidence rates were higher in the 65–74 and 75–84 age groups than in the 50–64 age group (2.24, 2.35, and 0.83 per 10,000 person-years, respectively) [ 11 ].

Patients younger than 79 years with morphologic AFF are more likely to have any risk factor other than age, such as bone metabolic disorders and skeletal dysplasia, should be excluded, especially when a patient is not treated with antiresorptive agents or glucocorticoids. In contrast, only one of the ten patients who used glucocorticoids had no other risk factors, thereby providing no evidence concerning the relationship between glucocorticoid use alone and AFF. Previously, Takahashi et al. reported that “antiresorptive treatment (> 3.5 years)” and “prior zoledronic acid treatment” were risk factors for developing AFF among bone metastatic patients with antiresorptive treatment [ 13 ]. The two denosumab cases with antiresorptive treatment in the current study suffered from breast cancer, and the durations of treatment (5 and 2 years) were shorter compared to the previous report (Supplementary Table  1 ).

Antiresorptive agents increase BMD by inhibiting bone resorption; nevertheless, long-term use increases the risk of AFF. It has been proposed that in the bones of antiresorptive agent users who develop AFF, the natural mechanism of dissipating energy and slowing crack propagation is impaired [ 43 ]. The main cause of AFF could be that microdamage in the lateral femoral cortex of the subtrochanteric region is not repaired in a timely fashion, due to the suppression of cortical bone remodeling by antiresorptive agents or the low rate of cortical bone remodeling in patients with metabolic bone diseases/skeletal dysplasia. Although the characteristic lateral periosteal callus forms normally, the gradual accumulation of unrepaired microdamage in the lateral femoral cortex leads first to unicortical fracture of the lateral femoral cortex and often thereafter to complete fracture through the medial cortex, at that point comprising a complete AFF. AFF occurs in patients with long-term antiresorptive agent use, pycnodysostosis, HPP, heterozygous loss-of-function variant with ALPL , and hypophosphatemic osteomalacia. On the other hand, although osteoblastic function could largely be low in patients with long-term antiresorptive agent use and pycnodysostosis, compensatory activation of osteoblasts with an increase in osteoid is seen in HPP, heterozygous loss-of-function variants with ALPL , and hypophosphatemic osteomalacia, and also seen is an elevated ALP in hypophosphatemic osteomalacia. Therefore, although remodeling of bone hard tissue is low, remodeling of bone matrix protein is activated in these disorders [ 19 , 44 , 45 ].

Usually, serum ALP level is low among the disorders and conditions with low bone turnover, such as the patients using glucocorticoid and antiresorptive drugs, HPP, and patients with heterozygous loss-of-function variants in ALPL , while high serum ALP levels are typically observed in the patients with hypophosphatemic osteomalacia due to compensatory activation of osteoblasts. Therefore, paying attention to serum ALP levels might facilitate the detection of latent causative bone metabolic disorders and skeletal dysplasia among some patients with morphologic AFF, although ALP is not a perfect indicator because its level varies depending on several other factors. A recent study by Ng et al. reported that among 1839 patients visiting an osteoporosis clinic, seven (0.4%) had persistently low serum ALP levels. Five patients were genetically diagnosed with HPP, including four patients with persistently low ALP levels [ 46 ]. Similarly, Alonso et al. reported that out of 3285 patients in the osteoporotic clinic, 16 had low serum ALP and 14 of the 16 had ALPL gene variants [ 37 ]. HPP is a skeletal dysplasia caused by heterozygous, compound heterozygous, or homozygous variants in ALPL encoding ALP. Symptoms of HPP show a wide range and mild cases only present low serum ALP, arthrosis, and musculoskeletal pain. Such cases are mainly associated with loss of heterozygous function of ALPL , which has been shown to be dominantly inherited and relatively frequent (one in 187) [ 47 , 48 , 49 , 50 ]. In 2012, Sutton et al. reported a case of bilateral subtrochanteric fracture after 4 years of bisphosphonate use for osteoporosis with mildly low serum ALP and later demonstrated a heterozygous variant in the ALPL gene (c.212G > A, p. Arg71His). Based on this result, it was suggested that administration of antiresorptive agents to osteoporotic patients with even heterozygous loss-of-function variants of ALPL should be carefully considered to avoid the development of subtrochanteric fractures [ 51 ]. In the present case with low serum ALP (patient #19), a heterozygous variant of ALPL is suspected, given the previous tibial fracture. However, even if serum ALP was decreased by other causes, low ALP itself could be associated with the risk of morphologic AFF. In 30 patients with ALP within the reference range, 19 (63%) had lower levels of ALP than the middle of the reference range, where elevation of ALP levels was expected due to active fractures. Given that ALP is usually supposed to elevate after a fracture due to enhanced bone remodeling at the fracture site, which may reflect low bone remodeling in all bone areas except the fracture site due to antiresorptive therapy [ 52 ].

The median serum Alb concentration in this cohort was relatively low (3.4 g/dL) compared with the reference value. Decreased food intake or absorption, decreased muscle mass, proinflammatory cytokines, acute illness, and comorbidities are common causes of hypoalbuminemia [ 53 ]. Considering that more than half of the patients in this study were older than 75 years, it is possible that low muscle mass and a greater complication rate of chronic inflammatory diseases contributed to low albumin levels.

To our knowledge, this is the first attempt to evaluate latent bone metabolic diseases and skeletal dysplasia associated with low bone formation comprehensively among patients with morphologic AFF in a single-center cohort. However, the sample size of this study was too small to predict the actual frequency of these bone diseases in morphologic AFF. Moreover, the genuine number of patients with these disorders in the current cohort was uncertain because it was a retrospective study, and some participants lacked pivotal data to conduct the differential diagnosis. For example, three, nine, and one patients were missing serum cCa, Pi, and ALP data, respectively.

Because of the retrospective nature of the current study, there were several analytical limitations. One of the limitations is a lack of information about the laboratory data relating to bone metabolism. For example, lack of measurement of 25-hydroxyvitamin D, which meant we could not evaluate the involvement of vitamin D deficiency in the development of AFF, which was reported elsewhere [ 54 ]. Inappropriately low BMD for age and sex without derangement of the bone metabolism-related laboratory measurements might suggest the possibility of mild osteogenesis imperfecta and related skeletal dysplasia [ 55 ]. Thus, in combination with genetic tests, screening for BMD might help evaluate the involvement of other skeletal dysplasia, including mild cases of osteogenesis imperfecta, in the development of morphologic AFF. In addition, since data collection was conducted on the electronic medical record in our hospital, past medical history, including past fractures, might be inaccurate. In the future, to clarify the genuine prevalence of bone disorders among patients with morphologic AFF, the execution of a comprehensive study with a large number of patients with morphologic AFF equipped with a completed laboratory dataset for all participants, and genetic testing if needed, is warranted.

When clinicians encounter patients with AFF, the careful exclusion of bone metabolic diseases and skeletal dysplasia associated with low bone formation should be conducted, since, in the cases of these disorders, appropriate treatment or elimination of the causative factor will reduce the risk of delayed union and recurrent fracture as those were observed in cases 1 and 2 in the current study. Furthermore, given that two out of the six patients with recurrent subtrochanteric fractures and two out of the five patients with subtrochanteric fractures on both sides had underlying bone metabolic disorders or skeletal dysplasia, in cases with these conditions, metabolic bone disease/skeletal dysplasia should be carefully differentiated. In addition, it is also desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients to reduce the risk of the development of morphologic AFF. To determine the subjects who require a screening for metabolic bone disease/skeletal dysplasia, it might be adequate to select subsets of patients with high or low fasting, antiresorptive-free, measurement of serum ALP [ 37 ]. It is also important to confirm that the change in ALP levels is persistent and not transient because only the long-term suppression of bone formation serves as a risk factor for developing morphologic AFF.

Data availability

All data generated or used during the study are available from the corresponding author and first author upon reasonable request.

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Soichiro Kimura, Takashi Sunouchi, Yoshitomo Hoshino, Naoko Hidaka, Hajime Kato, Masaomi Nangaku, Noriko Makita & Nobuaki Ito

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Supplementary file1 (PPTX 73.8 KB) Supplementary Figure 1 The graph presents the distribution of ALP levels among the 37 patients in the current study whose ALP levels were available. ALP levels were within the reference interval (between the mean ± 2 x standard deviation in normal subjects: 38-118 U/L) in 30 patients, lower than the reference interval in 2 (patients #13 and 19), and higher than the reference interval in 5 (patients #2, 8, 28, 34, and 35). The 4 patients diagnosed or suspected to be bone metabolic disease or skeletal dysplasia are indicated in bold letters with blue color. 74F to patient #7, 56M to patient #19, 53F to patient #32, and 48F corresponds to patient #34. Patient #8 was 15 years old, and the serum ALP level was within the reference range for their age. Supplementary Figure 2 The ROC and AUC for age were used to predict whether patients who developed morphologic AFF without any other risk factors except for age.

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Kimura, S., Sunouchi, T., Watanabe, S. et al. Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study. Osteoporos Int (2024). https://doi.org/10.1007/s00198-024-07168-4

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DOI : https://doi.org/10.1007/s00198-024-07168-4

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