Metabolic Bone Disease: An Overview

Abstract

Metabolic bone diseases are a heterogenous group of conditions that all result in aberrant bone mineral homeostasis with resulting skeletal disease. The underlying causes are variable, ranging from nutritional deficiencies to pathogenic variants in skeletal genes. To properly diagnose and treat these conditions, a clinician needs to understand bone metabolism as well as recognize the signs of disease in a patient. This review will focus on three relatively common metabolic bone diseases (osteogenesis imperfecta, hypophosphatasia, and X-linked hypophosphatemic rickets) that are caused by genetic variants, not by nutritional deficiency. As molecular DNA sequencing has improved, the scientific community has been able to better understand the genetic basis of these conditions and create sophisticated medical treatments based on the genetic deficiency.

Introduction

Bone is a living tissue which provides protection, shape, and support to several organ systems as well as the environment for blood cell production.

Bone is a composite material composed of both inorganic and organic elements; The inorganic component is primarily crystalline hydroxyapatite, [Ca3(PO4)2]3Ca(OH)2, while the organic component of bone comprises more than 30 proteins. Type I collagen is the most abundant of these proteins and exists as a triple-helical molecule of three polypeptide chains, each of approximately 1,000 amino acids in length. Two of these three polypeptide chains are identical α1(I) chains and the third one is a structurally similar α2(I) chain.¹ Non-collagenous proteins, such as glycoproteins and gamma-carboxyglutamic acid-containing proteins are thought to play roles in cell attachment, cell differentiation, and the regulation of hydroxyapatite minerals deposition.²

Bone is a metabolically active tissue which underoges modeling in the developing child and cycles of remodeling in adults to develop normal contours and maintain strength and mass, heal fractures, and function properly. Through this process, old bone is resorbed by osteoclasts and is replaced by new bone formed by osteoblasts.¹ Fibroblast growth factors, bone morphogenetic proteins, induction of the Wnt signaling pathway, osteoblast-specific transcription factor osterix (OSX), and receptor activator of the nuclear factor kappa-β ligand (RANKL) are all involved in pathways which affect this process. These pathways are regulated by hormones, cytokines and growth factors such as the parathyroid hormone, vitamin D, osteoprotegerin, sex hormones, fibroblast growth factor-23 (FGF23), and sclerostin.³ Osteocytes are additional bone cells which are responsible for regulating biomineralization, both by controlling osteoblast/osteoclast activity and by playing a role in phosphate metabolism.⁴ FGF23 is mainly produced by osteocytes and plays a critical role in human mineral ion homeostasis.⁵ Bone is the principal store for calcium and phosphate within the human body and is one of the main regulators of mineral metabolism.

During the last two decades remarkable therapies have been developed for rare metabolic bone disorders including hypophophatasia, and X-linked hypophosphatemia (also known as X-linked hypophosphatemic rickets in children). Other previously FDA-approved drugs for adults have been used off-label in pediatrics to great effect, especially in osteogenesis imperfecta and steroid induced osteopenia/osteoporosis.⁶ Additionally, newer drugs are in the pharmaceutical companies’ pipelines that may expand the metabolic bone therapy armamentarium and improve outcomes with safer therapies and fewer adverse side effects.

Osteogenesis Imperfecta

Case Report

A 15-year-old teenage boy was referred to genetics clinic due to a personal and family history of fracturing. Family reported at least two fractures per year recently, which was a decreased fracture incidence from when he was younger. His fractures have healed without deformity. He had to have hardware placed only once at age 13 years after an elbow fracture. The patient’s sister, mother, and maternal grandfather all have a history of recurrent fractures. No genetic testing has been done. Physical exam showed multiple surgical scars, but no bony deformities. Sclerae were blue grey. Dentition was normal.

DXA revealed osteopenia with Z-scores of −2.5 in spine and −2.8 in hip (normal +2.0 to −2.0). Initial laboratory workup included CMP, Mg, Phos, 25-OH vitamin D, PTH, osteocalcin, C-telopeptides (CTX), Procollagen type 1 Intact N-Terminal Propeptide (P1NP). Significant lab findings included alkaline phophatase activity of 395 U/L (reference range 70–260) and Osteocalcin of 213 ng/mL (reference range 19–159). Both these elevations indicate increased bone turnover.

Molecular genetic testing revealed a pathogenic variant in COL1A1. This is consistent with a diagnosis of osteogenesis imperfecta.

History of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) or “brittle bone disease” was identified in the partially mummified remains of an infant from 1,000 BCE Egypt and stories of Ivar the Boneless, a Viking leader who invaded Anglo-Saxon England in the 800s CE allude to possible OI.⁷ Other reports of brittle bones coupled with hearing loss appear in publications since the 1600s, though it was not until the mid-1800s when Vrolik described OI as a disease of congenital bone fragility separate from rickets. Later, associated reports of blue sclerae and deafness were connected to the condition.⁸

Description

Osteogenesis imperfecta (OI) is caused by pathogenic (disease causing) genetic variants in Type 1 collagen (approximately 85–90% of cases) and proteins that interact with Type 1 collagen (approximately 10–15% of cases)⁹. Type 1 collagen is one of the major support proteins of bone. Pathogenic variants in the genes for Type 1 collagen, COL1A1 and COL1A2, lead to a spectrum of phenotypes characterized by bone fragility with varying degrees of recurrent low impact fractures, tooth involvement called Dentinogenesis Imperfecta (DI), hearing loss, scoliosis, and short stature. OI is most commonly autosomal dominant when caused by pathogenic variants in the Type1 collagen genes (Figure 1). However, disease from variants in the collagen support genes can be recessive or X-linked (Figure 2). OI affects 1:10,000–20,000 and is pan-ethnic.¹⁰

Figure 1.

Autosomal Dominant Pedigree (Most OI/Some HPP)

Key: Shaded Affected; Unshaded Unaffected

Figure 2.

Autosomal Recessive Pedigree (some OI/some HPP)

Key: Shaded Affected; Unshaded Unaffected

There are a few ways to classify OI, with the Sillence Criteria being the classic model (Type I-Type IV) However, this has recently been revised to accommodate our improved understanding of the genetic causes of OI. With the advent of DNA sequencing, molecular/biochemical classification criteria have also been described. Transitioning to a mild, moderate and severe classification system with associated molecular information has been more clinically useful in recent years.¹¹

There is significant phenotypic heterogeneity among patients. Patients with mild OI may be diagnosed in childhood or adolescence, when their increased fracture burden becomes suspicious for an underlying pathology. DI, blue sclera, hearing loss and other minor features increase clinical suspicion. Severe patients often present prenatally with in-utero fractures and deformations. These patients will have progressive deformity with fractures and severely compromised bone growth. Their exam findings are striking and their clinical courses are notable for multiple orthopedic procedures and signficant growth impairment. Morbidity and sometimes mortality is due to respiratory distress. Over time, progressive scoliosis can worsen respiatory compromise and lead to stress on the cardiopulmonary system (Table 1).

Table 1.

Summary of Pertinent Findings

	Lab Abnormalities	Imaging	Inheritance	Exam Findings
OI	Elevated Alkaline Phosphatase if acute fracture	Hypomineralization, often multiple fractures in different states of healing	AD(autosomal dominant) rare AR (autosomal recessive) and X-linked	Blue sclerae, dentinogenesis imperfecta, long bone deformities
HPP	Low serum Alkaline Phosphatase High serum B6 High Urine PEA (phosphoethanolamine)	Perinatal/Infantile: severe hypomineralization, rickets, and long bone bowing Childhood: hypomineralization with radiolucent tongues Adult: Hypomineralization and Pseudofractures	AD or AR	Short stature, premature tooth loss with root intact, rickets, bowed legs, hypotonia, motor delay
XLH	Low serum phosphate Inappropriately normal or low calcitriol levels High serum FGF23	Wide physes and metaphyseal flaring of long bones, lower leg deformity	X-linked dominant	Short stature, wide joints, lower leg deformities, dental abscesses

An elevated alkaline phosphatase may occur in the setting of a recent fracture. Calcium, phosphorus, magnesium and vitamin D should all be normal.

Imaging findings vary depending on the phenotype. Mild OI patients may only have slight osteopenia and slender bones. Wormian bones, bony islands in the sutures of skull bones, can be seen in all severities of OI. Severe patients will also have osteopenia, bony deformities, thin ribs, poorly mineralized metaphases, and scoliosis. DXA scans demonstrate low bone mineral denisty.^12,13

Medical Treatment

Presently bisphoponates remainthe mainstay of medical treatment in children. Zoledronate and pamidronate are the most common IV bisphosphonates and alendronate is the most common oral bisphosphonate used in U.S.. Bisphophonates decrease osteoclast activity, so that osteoblast activity is unopposed. In OI patients, this leads to net positive cortical bone formation with improved bone density, but bone quality remains poor.¹³ Patients on bisphosphonate therapy will still fracture, although there is evidence that fewer vertebral compression fractures occur. Bone pain is usually improved with bisphophonate treatment, which can lead to patients becoming more active. Pediatric patients are usually medically treated until their growth plates close. Some adults with a significant fractures may require continued treatment. However, the persistent rate of long bone fractures leaves patients and providers dissatisfied and with hope for research on emerging novel therapies.^14,15

Anabolic therapies (drugs that stimulate bone formation), teriparatide and abaloparatide have been used off-label in clinical settings. Milder variants of OI have responded to teriparatide therapy but more severe variants did not.¹⁶ Two anti-sclerostin antibody therapies are presently undergoing formal clinical trials to determine if they will be helpful.¹⁷ Additionally, therapy with an anti-TGF-beta antibody is in clinical trials to treat OI.^14,15

Hypophosphatasia

Case Report

A two-week-old full term male infant was seen in skeletal dysplasia clinic with a history of an in-utero femur fracture. He was 7 pounds and 19 inches at birth. He did not require NICU care and went home with his mother from the newborn nursery. In clinic, his exam was was normal with no deformities of extremities. Alkaline phosphatase activity was remarkably low at 30 U/L (reference range 110–320), 25-OH vitamin D was 15 ng/mL (reference range 20–100), and vitamin B₆ was 437 mcg/liter (reference range 5–50). Skeletal survey showed osteopenia, healing femur fracture, and metaphyseal cupping and splaying. Molecular genetic testing showed biallelic pathogenic variants in ALPL. This is consistent with a diagnosis of infantile hypophosphatasia.

History of HPP

Hypophosphatasia (HPP) is the inborn error of metabolism caused by a low tissue-nonspecific alkaline phosphatase (TNSALP) activity resulting from deleterious variants in ALPL.¹⁸ Alkaline phosphatase was discovered in 1923 and is probably the most frequently tested human enzyme.¹⁹ HPP was first reported in 1948 by Dr. J.C. Rathbun in a 3-week-old patient noted to have wrist deformities and bowing of the femora, marked decalcification throughout the skeleton, and reduced serum alkaline phosphatase (ALP) activity. ²⁰ In 1953, premature tooth loss was attributed to the condition.²¹ In 1988, pathogenic variants in ALPL were attributed as the underlying etiology.²² There was no targeted treatment for this condition until 2015, when recombinant asfotase alpha obtained FDA approval under the brand name Strensiq.²³

Description of HPP

Impaired TNSALP activity leads to accumulation of it’s substrates in the body. One of these is inorganic pyrophosphate (PPi), which inhibits bone minrealization. High levels of PPi lead to the rachitic skeletal phenotype in HPP.²¹

HPP has a very wide phenotypic spectrum, ranging from life threatening bone demineralization in the fetus to isolated dental problems. The classic disease categories are perinatal severe, perinatal benign, infantile, severe childhood, mild childhood, adult and odonto.^18,24 The wide range of phenotypes correlates with different pathogenic gene variants. Over 400 pathogenic variants in ALPL are known.²⁴ Severe, early onset cases tend to have biallelic loss of function ALPL variants (autosomal recessive disease) and milder patients are more likely to have a single dominant negative ALPL variant (autosomal dominant disease) (Figures 1, 2). Perinatal cases are often identified via prenatal ultrasound due to polyhydramnios, bone demineralization, shortening of long bones, in-utero fractures, and pulmonary hypoplasia. These cases can be indistinguishable from severe OI in utero and were uniformly fatal prior to targeted therapy.²³ Vitamin B₆ associated seizures may occur in the most severe surviving patients.^18,24 Infantile and severe childhood HPP presents with obvious rickets, craniosynostosis, and faltering growth. Mild childhood to adult-onset cases are not always diagnosed due to the often subtle phenotype. Signs such as early tooth loss, low bone mineral density, increased fracture frequency, mild rachitic changes on radiographs along with poor exercise tolerance may not be noticed without a thorough diagnostic evaluation. All forms of HPP have early onset tooth loss, often with the root intact. Odontohypophosphatasia is limited to dental disease with generalized skeletal changes absent.²⁵

Significantly low alkaline phosphatase activity is the hallmark of the disease, often in single digits in perinatal and infantile cases. Vitamin B₆ levels will be elevated if the patient is not B₆ deficient, as B₆ is a substrate for TNSALP. ²⁶ Another substrate for TNSALP, phosphoethanolamine (PEA) may be elevated on urine amino acids, but is not as specific as vitamin B_6.²⁷

Imaging findings vary based on severity. Radiographs often show significant demineralization, splayed cranial sutures (undermineralized, but possibly still be fused), a rachitic rosary, flared metaphyses and long bone bowing. Many patients will develop characteristic “tongues of radiolucency” in the long bone metaphyses. Most patients have low bone mineral density.¹² Pseudofractures become common amongst adult patients²⁴ (Table 1).

Medical Treatment

Trials of a recombinant TNSALP-IgG molecule, asfotase alfa, started in 2008 in severe HPP patients with initial results published in 2012. The initial trial showed significant improvement in bone mineralization and motor skill acquisition with significant decreases in respiratory support and healing of rickets.²³ Asfotase alfa obtained FDA approval in 2015 for perinatal, infantile and childhood HPP as Strensiq. Asfotase alfa is given daily or every other day by subcutaneous injection. Treatment is life-long. Patients often have rapid gains in muscle strength and motor skills. Over time, rickets heal, joint deformities improve and mineralization normalizes. Side effects can be mild but most patients have injection site skin reactions and some may develop disfiguring skin atrophy and lipohypertrophy at injection sites.²⁸

X-linked Hypophosphatemic Rickets

Case Report

An 8 year-old girl was referred by an orthopedic surgeon to genetics clinic for genu varum. Mother first noted bowing when she started walking around age 1 year. She was initially diagnosed with multiple epiphyseal dysplasia at another hospital, but recently sought a second opinion from orthopedic surgery because of recurring knee pain. The orthopedic surgeon suspected a form of hereditary rickets. The patient’s mother had short stature, lower extremity bowing and joint pain. Exam revealed wide wrists and knees and tibial bowing. Laboratory evaulation was notable for serum phosphate of 3.3 mg/dL (reference range 3.5–6.8) and alkaline phosphatase of 346 U/L (reference range 110–320) Imaging studies included radiographs, which demonstrated metaphyseal cupping and fraying and DXA showed a normal bone density (Z score +2 in hip and spine). Molecular genetic testing identified a pathogenic variant in PHEX. The patient was started on burosumab therapy with consistent improvement in her rickets and hypophosphatemia.

History of X-Linked Hypophosphatemic

X-linked hypophosphatemic (XLH) rickets is the most common heritable form of rickets; XLH has an incidence of 1:20,000 live births and accounts for more than 80% of familial hypophosphatemic rickets.²⁹ In the late 1930s, Albright et al. reported a case of vitamin D resistant rickets. In the early 1970s, Bianchine et al. reported investigations of the rare phosphate-wasting disorder, autosomal dominant hypophosphatemic rickets (ADHR), which is phenotypically similar to XLH, elucidating the importance of FGF23 in ADHR. Later increased levels of FGF23 were found in many, but not all patients, with XLH.³⁰ Reports of [pathogenic] variants on the X chromosome’s PHEX gene in the mid-late 1990s provided additional insight into the pathophysiology of XLH.³¹

Description

XLH is caused by pathogenic variants in the PHEX gene and leads to high levels of the phosphatonin FGF23 in the blood. FGF23 functions to suppress phosphate reabsorption and alters Vitamin D synthesis, leading to renal phosphate wasting and inappropriately low Vitamin D³². Hypophosphatemia results in impaired apoptosis of the chondrocytes at the growth plate, leading to disorganization and impaired imeralization.³⁵ It has an incidence of between 1:20,000 and 1:60,000. Somewhat atypically for an X-linked condition, males and females are affected equally (Figure 3). Without treatment, XLH is progressively deforming. Patients develop lower leg deformities (genu valgum, genu varum, and windswept deformity are all seen), weakness, short stature, musculoskeletal pain and an abnormal gait. Dental abscesses, hearing loss and craniosynostosis can also complicate the disease course. Symptoms generally start in the toddler years, with leg bowing worsening when the child becomes weight bearing.^12,33 Laboratory evaluation will show low serum phosphate (best seen on fasting sample) and renal phosphate wasting on urine studies³⁴ (Table 1).

Figure 3.

X-linked Dominant Pedigree (XLH)

Key: Shaded Affected; Unshaded Unaffected

Medical Treatment

The landscape of medical treatment has enitrely changed in the last decade. XLH was traditionally treated with calcitriol (active vitamin D) and supplemental phosphate. This lessened the disease burden, but it was not curative. Treatment was burdensome as supplements needed to be given three to five times per day. Calcitriol and phosphate must be administered as a combined therapy or severe hyperparathyroidism can occur. A side effect of this treatment is nephrocalcinosis from higher serum and urine calciums levels. Many patients found frequent dosing challenging which limited the pharmacological response.^35,36

Burosumab is a monoclonal antibody to FGF23. Burosumab binds serum FGF23, leading to increased renal phosphate absorption. Therapy leads to normalization of serum phosphate, improved growth, improvment of rachitic skeletal abnormalties, less bone pain and improved gait.³⁶ In 2018, burosumab was FDA-approved therapy for all XLH patients over 6 months-old under the brand name Crysvita. Treatment consists of one subcutaneous injection every two weeks in pediatric patients and every four weeks in adult patients. However, some adult patients report better symptom control with an injection every two weeks. As with asfotase alfa, treatment is life-long. Burosumab is well tolerated by most patients. Common adverse effects include mild injection site reactions and restless leg syndrome. Hyperphosphatemia is rare.³⁶ Dental absecesses often remain a problem, despite treatment. A mild variant of XLH has been described and accounts for about 10% of all XLH patients in the U.S. and lower doses of burosumab normalize serum phosphate and heal the rickets.³⁷

Multidisciplinary Treatment in Metabolic Bone Disease

All patients with metabolic bone disease benefit from multidisciplinary care. A metabolic bone team often includes genetics, endocrinology, nephrology, orthopedic surgery, neurosurgery, physical medicine and rehabilitation, therapy services and dentistry.³⁸ Geneticists serve as rare disease experts, facilitate and interpret genetic testing, and may prescribe medical treatment. Due to the large role of hormones in bone and mineral homeostatsis, endocrinologists often follow these patients and may also prescribe medical treatment. Nephrologists often follow patients with a renal component of their disease such as renal phosphate wasting in XLH and those at risk for nephrocalcinosis. Orthopedic surgeons should follow patients at risk for fracture or those with deformtiies that may require surgical intervention. Neurosurgeons often follows patients with spinal involvement or with potential CNS complications such as basilar invagination in OI. Physical medicine and rehabilitation doctors help with non-operative modalities like bracing and injections, prescribing and fitting medical devices, and managing pain medication. Physical therapy and occupational therapy sees most patients with a metabolic bone disease to help with motor skills and for rehabilitation after injury or surgery. Dental services are needed for patients with metabolic bone disease as the teeth are often affected and patients may need significant dental interventions.

Conclusion

Metabolic bone diseases, although rare, have spurned the creation of sophisticated new drugs that target disease at its molecular level. Due to bone’s constant remodeling, medications are able to alter impaired pathways to improve or correct bone metabolism. This is significant area of new drug development and there are multiple ongoing clinical trials. This will result in a new armament of medications that will improve the lives of patients with a wide variety of bone diseases.